Pancreatobiliary Pathology Society Journal Watch
October November 2018
Last Update on 2018-12-17
PBPath Journal Watch Articles
Wellcome to the PBPath Journal Watch!
This bi-monthly journal watch features exciting recently published pancreas and biliary pathology articles that will provide up to date medical knowledge in our field. These articles will be showcased in several convenient categories, including surgical pathology, molecular pathology and cytopathology among others. The articles in each category are in no particular order.
Previous months’ issues may be found in our archive.
We encourage members to actively participate by recommending new articles and providing feedback using the forms provided.
We hope that you will enjoy the new PBPath Journal Watch!
Surgical Pathology
Pancreas
Morphology, Diagnostics, IHC
Morphology, Diagnostics, IHC
- Pancreatic cancer arising in the remnant pancreas is not always a relapse of the preceding primary
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30467323
This study aimed to understand the biology of pancreatic ductal adenocarcinoma that arises in the remnant pancreas after surgical resection of a primary pancreatic ductal adenocarcinoma, using integrated histological and molecular analysis. Patients who underwent a completion pancreatectomy for local recurrence following resection of a primary pancreatic ductal adenocarcinoma were studied with histological analysis and next-generation sequencing of the primary and the recurrent cancer. Of six patients that met the inclusion criteria, three cases were classified as “true” recurrences, i.e., the primary and the cancer in the remnant pancreas shared both morphological features and molecular alterations. Two cases were identified as having independent cancers that exhibited different histological and molecular profiles. In the remaining case, the relationship could not be determined. Pancreatic ductal adenocarcinoma that arises in the remnant pancreas can be either a second primary or a “true” relapse of the preceding primary. The differentiation of second primaries from local recurrences may have important implications for patient management.
- Epidermoid cyst in intrapancreatic accessory spleen: A systematic review
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30366677
BACKGROUND/OBJECTIVES: Due to its rarity, epidermoid cyst in intrapancreatic accessory spleen (ECIPAS) is still a diagnostic dilemma during clinical practice. The aim of this review was to summarize the epidemiologic features and management of ECIPAS. METHODS: MEDLINE and EMBASE were searched for English articles reporting on ECIPAS up to April 30th, 2018 following the methodology suggested by the PRISMA guidelines. Categorical variables were reported as frequency and percentage. Continuous variables were reported as median (range). RESULTS: A total of 56 patients from 47 full articles were included for the final data synthesis. More than half of the ECIPASs (59%) were found incidentally. The female/male ratio was 1.33. ECIPAS is typically a single mono-/multi-lobular cystic lesions in the pancreatic tail with thickened cystic wall or various amount of solid component which had identical density/signal to the spleen on imaging examinations. The cyst is filled with serous or non-serous fluid. Recognition of the surrounding ectopic splenic tissue is the key point to diagnose ECIPAS. However, no preoperative examination was able to make a definite diagnosis. Almost all the patients (96%) received surgical treatment, due to the suspicion of pancreatic malignant or potentially malignant cystic tumor, especially mucinous cystic neoplasm (MCN). CONCLUSIONS: Although seldom encountered, ECIPAS should be considered as a differential diagnosis for pancreatic cystic lesions, especially when solid component was detected. As a benign disease, unnecessary surgery should be avoided. Because it is difficult to make a definite diagnosis preoperatively by one single examination, multiple modalities may be required.
- Pancreatic extragastrointestinal stromal tumor invading the duodenum
Turkish journal of surgery 2018 01;34(3):231-233
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30302427
Extragastrointestinal stromal tumors that arise in the pancreas are extremely rare and managing them can be difficult, particularly if located in the head of pancreas. This case report aims to contribute to the existing data in the literature regarding extragastrointestinal stromal tumors with rare and unusual locations. We present a 56-year-old man who presented with recurrent mild right upper quadrant abdominal pain. Abdominal computed tomography and magnetic resonance imaging revealed a mass lesion with a diameter of 10 cm localized in the head of pancreas. Pancreaticoduodenectomy with complete tumor excision was performed. He was discharged on the postoperative day 14. Only 15 extragastrointestinal stromal tumors cases have been reported. Of these 15 cases, tumors were located in the head of pancreas in six cases. Here we report the seventh case of pancreatic extragastrointestinal stromal tumor arising in the head of pancreas and also the largest of these seven tumors.
- The expression of death receptor systems TRAIL-R1/-R2/-R4, CD95 and TNF-R1 and their cognate ligands in pancreatic ductal adenocarcinoma
Histology and histopathology 2018 Oct;():18054
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30375637
The expression of five members of the TNF receptor superfamily and two of their ligands in human pancreatic ductal adenocarcinoma were investigated in parallel by immunohistochemistry. 41 patients with histologically confirmed ductal carcinoma of the pancreas were enrolled in this study in order (i) to compare the individual TNFR-SF expression and their ligands in PDAC-cells and (ii) to investigate their correlation with survival data. All patients had undergone pancreaticoduodenectomy and were staged as pT3N1M0. Immunostaining was done on FFPE tissue sections of the tumor tissue, using antibodies directed against TRAIL-Receptor-1, -2 and -4, TRAIL, CD95, TNF-Receptor-1 and TNF-α. The intensity and quantity of immunostaining were evaluated separately for tumor cell cytoplasm and tumor cell nucleus. Immunostaining results were correlated with each other and with patient survival. All proteins were found to be expressed in the majority of the tumor cells. The expression (i) of the following members of TNFR-SF and their ligands correlated with each other: TNF-Receptor-1 and TNFα (cytoplasmatic scores, p=0.001), TNF-Receptor 1 and TRAIL (nuclear antigen expression p=0.005 and the main score p=0.001, which contains the overall intracellular antigen expression), TNF-Receptor 1 and CD95 (main score, p=0.001), TRAIL-Receptor-1 and TRAIL-Receptor-2 (nuclear parameters, p=0.023), TRAIL-Receptor-4 and TRAIL (main score p=0.041). In addition (ii), high cytoplasmatic expression of TNF-Receptor-1 and a strong cytoplasmatic and nuclear expression of CD95 correlated significantly with a better prognosis of the PDAC patients.
- Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer
British journal of cancer 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30377341
BACKGROUND: Pancreatic cancer (PC) hijacks innate cellular processes to promote cancer growth. We hypothesized that PC exploits PD-1/PD-L1 not only to avoid immune responses, but to directly enhance growth. We also hypothesized that immune checkpoint inhibitors (ICIs) have direct cytotoxicity in PC. We sought to elucidate therapeutic targeting of PD-1/PD-L1. METHODS: PD-1 was assessed in PC cells, patient-derived organoids (PDOs), and clinical tissues. Then, PC cells were exposed to PD-L1 to evaluate proliferation. To test PD-1/PD-L1 signaling, cells were exposed to PD-L1 and MAPK was examined. Radio-immunoconjugates with anti-PD-1 drugs were developed to test uptake in patient-derived tumor xenografts (PDTXs). Next, PD-1 function was assessed by xenografting PD-1-knockdown cells. Finally, PC models were exposed to ICIs. RESULTS: PD-1 expression was demonstrated in PCs. PD-L1 exposure increased proliferation and activated MAPK. Imaging PDTXs revealed uptake of radio-immunoconjugates. PD-1 knockdown in vivo revealed 67% smaller volumes than controls. Finally, ICI treatment of both PDOs/PDTXs demonstrated cytotoxicity and anti-MEK1/2 combined with anti-PD-1 drugs produced highest cytotoxicity in PDOs/PDTXs. CONCLUSIONS: Our data reveal PCs innately express PD-1 and activate druggable oncogenic pathways supporting PDAC growth. Strategies directly targeting PC with novel ICI regimens may work with adaptive immune responses for optimal cytotoxicity.
- High nuclear Survivin expression as a poor prognostic marker in pancreatic ductal adenocarcinoma
Journal of surgical oncology 2018 Dec;118(7):1115-1121
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30261114
BACKGROUND: Survivin, one of the key regulators of mitosis and apoptosis, has long been well recognized to play important biological roles in many neoplasms, including pancreatic ductal adenocarcinoma (PDAC). However, its prognostic value in PDAC remains controversial. PATIENTS AND METHODS: Nuclear expression of Survivin was detected, using tissue microarray-based immunohistochemistry, in paired-tumor and nontumor samples from 306 patients with radically resected PDAC. The staining H scores were further correlated with clinicopathologic features and disease-specific survival (DSS). RESULTS: Nuclear Survivin expression was much higher in tumor than in nontumor tissues (P < 0.001). No significant association between tumoral Survivin expression and clinicopathologic variables was found. For prognosis, high Survivin expression was associated with shortened DSS in all eligible patients and four subgroups, that is, male and nondiabetic patients as well as those with head-located and G1-2 tumors, shown by univariate analyses. In addition, a statistically marginal significance was revealed in eight subgroups. For the entire cohort and two subgroups, nuclear Survivin expression was also multivariate identified as an independent predictor for DSS. For patients with G1-2 tumors, it was the single prognostic marker. CONCLUSION: Our data suggest an association between high nuclear Survivin expression and poor prognosis in PDAC. However, further confirmation might be necessary.
- Residual Tumor Index: A Prognostically Significant Pathologic Parameter in Neoadjuvant-treated Pancreatic Ductal Adenocarcinoma
- Overexpression of folate receptor alpha is an independent prognostic factor for outcomes of pancreatic cancer patients
https://link.springer.com/article/10.1007/s00795-018-0197-8
- Solitary pancreatic metastasis of extremity myxoid liposarcoma: a case report and literature review
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-5059-1
- PD-L1 expression in pancreatic adenosquamous carcinoma: PD-L1 expression is limited to the squamous component
Pathology, research and practice 2018 Dec;214(12):2069-2074
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30477643
AIM: We examined the programmed death-ligand 1 (PD-L1) expression in surgically resected pancreatic adenosquamous carcinoma (PASC) samples. Furthermore, the detection rate was also assessed using biopsy cases obtained from endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). METHODS: Fifteen cases of PASC (six resected and nine EUS-FNA biopsied) from the Kurume University Hospital between 2009 and 2016 were used for the evaluation of PD-L1 expression. As a control group, 34 cases of pancreatic ductal adenocarcinomas (PDACs) were selected. To compare the positivity and intensity of PD-L1, two types of clones (SP263, E1L3N) were examined for immunostaining. Only the membrane expression of PD-L1 was regarded as positive. The PD-L1 expressions in the squamous cell carcinoma component (SCc), adenocarcinoma component (ACc), and immune cells were assessed separately. The ratio of PD-L1 expression was calculated by counting the positive tumor cells, and tumor proportion score (TPS) was applied (TPS; Null < 1%, low expression; 1 ≤ TPS ≤ 49% and high expression; ≥ 50%). RESULTS: PD-L1 expression was observed in five surgical PASC samples (83%). This shows that SCc presented a high expression in these cases. However, the overall TPS indicated a low expression. In contrast, only one case (3%) was positive for PD-L1 in PDACs, and the TPS indicated a low expression. No differences in PD-L1 expression were observed between the two clones, SP263 and E1L3N. High PD-L1 expression in the EUS-FNA sample was found in only one case (11%). DISCUSSION: Although assessment using the tumor cells of PASC samples obtained from EUS-FNA was difficult, this study suggests the selective expression of PD-L1 in the SCc of PASC. Furthermore, it was considered that immune checkpoint inhibitors could provide therapeutic effects selectively on the SCc for the entire range of TPSs, though the PD-L1 expression was low.
Staging
Pancreas TNM staging, Margins, Survival
- ASO Author Reflections: Even in Pancreatic Cancer, not all N Diseases are Created Equal
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30284129
- International Validation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) TNM Staging System in Patients With Resected Pancreatic Cancer
JAMA surgery 2018 Oct;():e183617
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30285076
Importance: The recently released eighth edition of the American Joint Committee on Cancer TNM staging system for pancreatic cancer seeks to improve prognostic accuracy but lacks international validation. Objective: To validate the eighth edition of the American Joint Committee on Cancer TNM staging system in an international cohort of patients with resected pancreatic ductal adenocarcinoma. Design, Setting, and Participants: This international multicenter cohort study took place in 5 tertiary centers in Europe and the United States from 2000 to 2015. Patients who underwent pancreatoduodenectomy for nonmetastatic pancreatic ductal adenocarcinoma were eligible. Data analysis took place from December 2017 to April 2018. Exposures: Patients were retrospectively staged according to the seventh and eighth editions of the TNM staging system. Main Outcomes and Measures: Prognostic accuracy on survival rates, assessed by Kaplan-Meier and multivariate Cox proportional hazards analyses and concordance statistics. Results: A total of 1525 consecutive patients were included (median [IQR] age, 66 (58-72) years; 802 (52.6%) male). Distribution among stages via the seventh edition was stage IA in 41 patients (2.7%), stage IB in 42 (2.8%), stage IIA in 200 (13.1%), stage IIB in 1229 (80.6%), and stage III in 12 (0.8%); this changed with use of the eighth edition to stage IA in 118 patients (7.7%), stage IB in 144 (9.4%), stage IIA in 22 (1.4%), stage IIB in 643 (42.2%), and stage III in 598 (39.2%). With the eighth edition, 774 patients (50.8%) migrated to a different stage; 183 (12.0%) were reclassified to a lower stage and 591 (38.8%) to a higher stage. Median overall survival for the entire cohort was 24.4 months (95% CI, 23.4-26.2 months). On Kaplan-Meier analysis, 5-year survival rates changed from 38.2% for patients in stage IA, 34.7% in IB, 35.3% in IIA, 16.5% in IIB, and 0% in stage III (log-rank P < .001) via classification with the seventh edition to 39.2% for patients in stage IA, 33.9% in IB, 27.6% in IIA, 21.0% in IIB, and 10.8% in stage III (log-rank P < .001) with the eighth edition. For patients who were node negative, the T stage was not associated with prognostication of survival in either edition. In the eighth edition, the N stage was associated with 5-year survival rates of 35.6% in N0, 20.8% in N1, and 10.9% in N2 (log-rank P < .001). The C statistic improved from 0.55 (95% CI, 0.53-0.57) for the seventh edition to 0.57 (95% CI, 0.55-0.60) for the eighth edition. Conclusions and Relevance: The eighth edition of the TNM staging system demonstrated a more equal distribution among stages and a modestly increased prognostic accuracy in patients with resected pancreatic ductal adenocarcinoma compared with the seventh edition. The revised T stage remains poorly associated with survival, whereas the revised N stage is highly prognostic.
- A Refined Staging Model for Resectable Pancreatic Ductal Adenocarcinoma Incorporating Examined Lymph Nodes, Location of Tumor and Positive Lymph Nodes Ratio
Journal of Cancer 2018 09;9(19):3507-3514
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30310507
Background: Nodal status and tumor site are prognostic factors for resectable pancreatic ductal adenocarcinoma (PDAC). Parameters for nodal status are diverse, and the number of examined lymph nodes (eNs) needed for good prognosis are uncertain. We try to modify staging system of resectable PDAC with parameters mentioned above by recursive partitioning analysis. Methods: Patients from the Surveillance, Epidemiology, and End Results (SEER) database were divided into training cohort and internal validation cohort, randomly. PDAC patients from Sun Yat-sen University Cancer Center were regarded as external validation cohort. The training cohort was used to refine staging model by recursive partitioning analysis, while the internal validation cohort and the external validation cohort were applied to assess discriminatory capacity of staging model. For parameters included in the modified model, their effects were studied. Results: The number of eNs, tumor site and tumor size were risk factors for positive nodal status. Lymph nodes ratio (LNR), tumor site, eNs and T stages of 8th the American Joint Committee on Cancer (AJCC) were selected to develop a refined model, dividing patients into 5 groups of different outcomes, preceding 8th AJCC classification. Besides, we found that (1) for small PDAC (diameter < 1cm), lymph node metastasis was rarely found; (2) enough eNs were needed to ensure better prognosis of node-negative patients; (3) tumors in the head of pancreas were prone to lymph nodes metastasis; (4) for node-positive patients, LNR was a better nodal parameter compared to positive lymph nodes (pNs). Conclusion: Our improved staging system helps to illuminate the interactions among tumor site, size and eNs.
- Evaluation of the prognostic value of the new AJCC 8th edition staging system for patients with pancreatic adenocarcinoma; a need to subclassify stage III?
European journal of cancer (Oxford, England : 1990) 2018 Nov;104():62-69
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30326370
BACKGROUND: There have been several proposed changes for the 8th edition of the American Joint Commission on Cancer (AJCC) for pancreatic adenocarcinoma. The aim of this study was to evaluate the prognostic value of the new staging system for patients with pancreatic adenocarcinoma, especially in stage III patients. METHODS: We analysed the data of patients newly diagnosed with pancreatic adenocarcinoma between 2008 and 2016 at our hospital. Patients were staged according to 7th edition AJCC criteria, as well as the new 8th edition staging system. The pathologic stage was used in the surgical cases, and the clinical stage, determined by radiographic findings, was used in the unresectable cases. RESULTS: Five hundred two patients were identified who met the inclusion criteria. In node-negative patients, there were no significant differences in survival among T 1, 2 and 3 groups according to the 8th edition. The survival rates of patients with N1 (1-3 positive nodes) and N2 (≥4 positive nodes) disease, according to 8th edition, were significantly different (p < 0.001). Although N2 and T4 patients are both stage III according to the new staging system, N2 patients had a better survival rate than T4 patients (p = 0.038). The new staging system stratifies patients more evenly across stages without sacrificing the prognostic accuracy. CONCLUSIONS: The AJCC 8th edition has some advantages over the previous version. However, patients with N2 and T4, who have been integrated into stage III, showed different treatment modalities and prognoses, and we proposed dividing stage III into IIIA (T1-3N2M0) and IIIB (T4NanyM0).
- Prognostic Impact of Portal System Invasion in Pancreatic Cancer Based on Image Classification
Pancreas 2018 10;47(10):1350-1356
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30286011
OBJECTIVES: This study aimed to clarify the correlation between image classification and the pathological degree of portal system invasion (PSI) and to evaluate the prognostic impact of PSI in pancreatic cancer (PC). METHODS: Pancreatic cancer patients with surgical resections (head, n = 244; body and tail, n = 80) were enrolled in this study. RESULTS: Based on imaging findings, portal vein (PV) invasion was classified as type A (absent), B (unilateral narrowing), C (bilateral narrowing), or D (stenosis or obstruction with collaterals). Splenic vein (SPV) invasion was classified as type α (absent), β (stenosis), or γ (obstruction). The pathological grade of venous invasion was classified as grade 0 (no invasion), 1 (tunica adventitia), 2 (tunica media), or 3 (tunica intima). In PV and SPV invasions, image classification and pathological grade showed significant correlation (PV: ρ = 0.696; SPV: ρ = 0.681). Patients with PV invasion deeper than type B exhibited significantly poorer survival than type A (P < 0.0001). In contrast, there was no difference in survival among types α, β, and γ. CONCLUSIONS: Image classification was correlated with the pathological grade of PSI in PC. Although not applicable for SPV invasion, image classification of PV invasion is a robust indicator for PC prognosis.
- Intra-Operative Frozen Section Histology of the Pancreatic Resection Margins and Clinical Outcome of Patients with Adenocarcinoma of the Head of the Pancreas Undergoing Pancreaticoduodenectomy
Medical science monitor : international medical journal of experimental and clinical research 2018 Jul;24():4905-4913
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30007990
BACKGROUND The aim of this study was to compare the clinical outcome in patients with pancreatic ductal adenocarcinoma who underwent frozen section and paraffin section histology of the surgical resection margins during pancreaticoduodenectomy. MATERIAL AND METHODS Frozen section and routine paraffin section histopathology were performed using the following categories: R0 (no tumor cells at the surgical resection margin), R1 (tumor cells at, or within 1 mm, of the surgical resection margin), and R2 (tumor seen macroscopically at the surgical resection margin). R1 and R2 patients underwent additional resection to achieve R0. RESULTS Of 346 patients who underwent pancreaticoduodenectomy, frozen section histology showed positive resection margins in 22 patients (9.2%) and paraffin section histology was positive in 20 patients (8.4%). The OS was nine months in frozen section-positive patients and 20 months in frozen section-negative patients (p=0.001). The OS rates were significantly different between the paraffin section-positive and paraffin section-negative patients (11 months vs. 21 months) (p=0.001). Univariate and multivariate analysis showed that increased tumor size, high tumor grade, lymph node metastases, a positive superior mesenteric artery and retroperitoneal margin, and a positive resection margin on frozen section were significantly correlated with reduced OS (p<0.05). Twenty-two patients with positive resection margins on frozen section histology underwent further resection; R0 was achieved in 14 patients, with no significant difference in OS. CONCLUSIONS For patients who underwent pancreaticoduodenectomy for pancreatic carcinoma with positive resection margins on frozen section, further surgical resection to achieve R0 had no significant positive impact on OS.
- Definition of an extended minimum level of lymphadenectomy in non-pancreatic periampullary cancer resections
- A Refined Staging Model for Resectable Pancreatic Ductal Adenocarcinoma Incorporating Examined Lymph Nodes, Location of Tumor and Positive Lymph Nodes Ratio
- Nomogram to Predict Cancer-Specific Survival in Patients with Pancreatic Acinar Cell Carcinoma: A Competing Risk Analysis
- The incidence and survival of pancreatic cancer by histology, including rare subtypes: a nation‐wide cancer registry‐based study from Taiwan
https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.1795
- Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches: Autoimmune diseases and pancreatic cancer risk
- ASO Author Reflections: Staging Laparoscopy Improves Overall Survival of Patients with Pancreatic Adenocarcinoma Found to Have Occult Metastatic Disease
Annals of surgical oncology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30430323
- Minimally Invasive Staging Surgery for Cancer
https://www.surgonc.theclinics.com/article/S1055-3207(18)30677-X/fulltext
- Risk factors related to metastasis of para-aortic lymph nodes in pancreatic ductal adenocarcinoma: A retrospective observational study
- Impact of tumor size on survival of patients with resected pancreatic ductal adenocarcinoma: a systematic review and meta-analysis
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4901-9
- The New American Joint Committee on Cancer TNM Staging System for Pancreatic Cancer—Balancing Usefulness With Prognostication
https://jamanetwork.com/journals/jamasurgery/fullarticle/2705293
- International Validation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) TNM Staging System in Patients With Resected Pancreatic Cancer
https://jamanetwork.com/journals/jamasurgery/fullarticle/2705296
- Evaluation of the prognostic value of the new AJCC 8th edition staging system for patients with pancreatic adenocarcinoma; a need to subclassify stage III?
https://www.sciencedirect.com/science/article/pii/S0959804918313686
- Role of adjuvant therapy in resected stage IA subcentimeter (T1a/T1b) pancreatic cancer
Cancer 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30457666
BACKGROUND: The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB). METHODS: A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment. RESULTS: A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring <1 cm (T1a/T1b). Approximately 94.2% of patients had negative surgical margins (815 patients) and 46.9% (410 patients) received adjuvant therapy. The median OS was significantly different for patients who received adjuvant therapy compared with patients who did not (70.7 months vs 46.9 months; P=.0001). For patients with tumors measuring <1 cm, survival was not found to be significantly different between patients who received adjuvant treatment compared with those who did not (not reached vs 85.3 months; P=.54). In the multivariable analysis, none of the covariates (treatment group, Charlson-Deyo Score, age, insurance, and facility status) demonstrated significant differences for patients with tumors measuring <1 cm. CONCLUSIONS: The current study is the first to demonstrate no survival benefit for adjuvant therapy in patients with resected subcentimeter PDAC.
- Incidence and risk factors for abdominal occult metastatic disease in patients with pancreatic adenocarcinoma
https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25288
- Reappraising the Concept of Conditional Survival After Pancreatectomy for Ductal Adenocarcinoma: A Bi-institutional Analysis
Annals of surgery 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30339622
OBJECTIVE: To reappraise the concept of conditional survival (CS) following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), accounting for the patient’s present disease status relative to recurrence. BACKGROUND: CS, defined as the probability of surviving an additional time frame based on accrued lifespan, offers dynamic survival projections as compared with baseline overall survival. METHODS: Patients undergoing pancreatectomy for PDAC at 2 institutions from 2000 to 2013 were retrospectively analyzed. The 12-month CS was estimated separately for patients who were disease-free or with recurrence at the given time points. Next, the conditional probability of reaching 60-months of survival was examined in each conditioning set across strata of prognostic covariates, including American Joint Committee on Cancer stage, tumor grade, R-status, and adjuvant treatment. RESULTS: The study population consisted of 1005 patients. In disease-free patients, the 12-month CS increased as a function of time already survived, showing an opposite trend compared with overall survival. In patients who recurred, the 12-month CS was lower than the disease-free counterpart, especially within 24 months postoperatively. When stratifying by the levels of prognostic covariates, the 60-months CS estimates for disease-free patients tended to level off progressively, indicating that factors independently associated with survival at the time of pancreatectomy lost power over time. This concept did not apply to the conditioning set of patients with recurrence, where CS estimates across variables strata diverged with accrued lifespan. CONCLUSION: This paper provides new information on how prognosis following pancreatectomy for PDAC evolves over time, adjusting for the time the patient already survived, and for the patient’s present disease status relative to recurrence.
- Association Between Very Small Tumor Size and Decreased Overall Survival in Node-Positive Pancreatic Cancer
Annals of surgical oncology 2018 Dec;25(13):4027-4034
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30298331
BACKGROUND: In pancreatic adenocarcinoma (PDAC), increasing tumor size usually correlates with a worse prognosis. However, patients with a very small primary tumor who experience lymph node involvement may have a different disease biology. This study sought to determine the interaction between tumor size and lymph node involvement in terms of overall survival (OS). METHODS: The study identified 17,073 patients with a diagnosis of M0 resected PDAC between 1983 and 2013 using the Surveillance, Epidemiology, and End Results database. The patients were stratified by lymph node involvement (N0 vs N+) and T stage (T1a-T1b vs T1c vs T2 vs T3 vs T4). The Kaplan-Meier method was used to estimate OS, and Cox regression analysis was used to compare survival between subgroups after adjustment for patient-specific factors. RESULTS: Lymph node involvement and T stage significantly interacted (p < 0.001). Among the patients with node-negative disease, 5-year OS decreased monotonically with increasing T stage (59.1%, 30.6%, 22.9%, 16.6%, and 8.0%, respectively; p < 0.001). In contrast, among the patients with node-positive disease, those with T1a-T1b tumors (< 10 mm) had worse 5-year OS than those with T1c tumors (7.4% vs 17.6%; adjusted hazard ratio, 0.70; 95% confidence interval, 0.50-0.97; p = 0.034) and similar survival compared with those who had T2, T3, or T4 tumors (9.7%, 8.2%, and 4.8%, respectively; p > 0.2 in all cases). CONCLUSIONS: Among patients with lymph node-positive PDAC, very small primary tumors are associated with decreased OS. This finding raises the possibility that small tumors capable of lymph node metastasis might represent more biologically aggressive cancers.
- Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study
BMC medicine 2018 08;16(1):125
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30126408
BACKGROUND: The prognosis of pancreatic cancer (PaC) strongly varies across different stages and age groups, which has unfortunately not been well recorded in the literature. This international population-based study aimed to provide tumor-node-metastasis (TNM) stage- and age-specific survival estimates and trends in resected and overall (resected and unresected) PaC in the early twenty-first century. METHODS: Using data from the US Surveillance, Epidemiology, and End Results-18 Program and the national cancer registries of the Netherlands, Belgium, Norway, and Slovenia, short-term and long-term overall survival results stratified by TNM stage and age in resected and overall primary PaC, irrespective of being microscopically confirmed or not, in 2003-2014 were computed using the Kaplan-Meier method. The temporal survival trends over three predefined periods (2003-2005, 2006-2008, and 2009-2011) were further examined using the log-rank test. RESULTS: In total, data for 125,183 patients were analyzed. Overall, age-stratified 3-year survival was 20-34% (< 60 years), 14-25% (60-69 years), and 9-13% (≥ 70 years) in stages I-II PaC; and 2-5% (< 60 years), 1-2% (60-69 years), and < 1-1% (≥ 70 years) in stages III-IV cancer. Patients who underwent operation had higher 3-year survival in each stage and age group (stages I-II: 23-39% (< 60 years), 16-31% (60-69 years), and 17-30% (≥ 70 years); stages III-IV: 5-19% (< 70 years) and 2-14% (≥ 70 years)). Perioperative survival also decreased with advancing stage and older age (stages I-II: 98-100% (< 60 years), 97-99% (60-69 years), and 94-99% (≥ 70 years); stages III-IV: 94-99% (< 70 years) and 81-96% (≥ 70 years)). Between 2003 and 2005 and 2009-2011, for overall PaC, both short-term and long-term survival improvements were observed in all countries except Belgium; for resected disease, short-term improvements were present only in the USA and Slovenia, but long-term improvements were observed in all countries except Slovenia, with stage-specific variations. CONCLUSIONS: Our large international study provides TNM stage- and age-specific population-based survival in overall and resected PaC that will facilitate clinical counseling. While the survival expectations for patients with resected PaC are substantially higher than the widely available and known dismal survival predictions for overall patients, conclusions on the benefits of resection cannot be made from this observational study. Patients with advanced-stage disease and/or older age should undergo careful risk assessment before treatment. Limited but inspiring improvement in survival is observed.
Macroscopy
Macroscopy / Grossing
- Evaluation of All Surgical Margins in Pancreatic Resection Specimens by Proper Grossing Techniques: Surgical Pathology Experience of 285 Cases
Turk patoloji dergisi 2018 4;34(3):242-246
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29630087
OBJECTIVE: The aim of this study was to review our series of pancreatic resection specimen handling results and focus on the positivity of the tumor in various retroperitoneal surgical margins. MATERIAL AND METHOD: Our archival cases from 2008 to 2018 were retrospectively examined, especially for the surgical margins. The demographics, tumor locations, and the diagnoses were recorded. The state of all of the retropancreatic surgical margins (anterior, posterior, superior, inferior, superior mesenteric vein and artery) were recorded. RESULTS: There were 285 cases, of which 157 were male and 128 female. The mean and median ages were 63.3 and 64, respectively. Invasive ductal adenocarcinoma was the most common diagnosis [202 cases (70.8%)]. Positivity was observed in 90 (31.5%) margins. The majority was in the superior mesenteric vein margin [n:24 (8.4%)]. This was followed by the anterior, resection and SMA margins. CONCLUSION: Pancreatic resections should macroscopically be sampled by recommended methods in order to detect positivity in individual margins by proper grossing techniques. When this is applied, the superior mesenteric vein margin is the margin most prone to be positive for the tumor.
- Incidence and risk factors for abdominal occult metastatic disease in patients with pancreatic adenocarcinoma
Journal of surgical oncology 2018 Dec;118(8):1277-1284
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30380143
BACKGROUND: The incidence of occult metastatic disease (OMD) in pancreatic ductal adenocarcinoma (PDAC) and associated risk factors are largely unknown. METHODS: We identified all patients with PDAC, who had an aborted oncologic operation due to OMD within a 10-year period. The cases were matched to a cohort of resected PDAC patients on a 1:3 ratio, based on age and sex, for comparison of preoperative clinical characteristics and potential risk factors for OMD. RESULTS: In the studied period, 117 patients with OMD were identified in 1423 pancreatectomies performed for PDAC (8%). Liver metastases were the most common finding (79%) followed by peritoneal implants (16%). When compared with non-OMD cases, patients with OMD presented more often with abdominal pain (P < 0.001), and higher preoperative carbohydrate antigen 19-9 (CA 19-9) values ( P = 0.007). Additionally, indeterminate liver lesions on preoperative computed tomography (CT) were identified in 40% of OMD versus 17% of non-OMD patients ( P < 0.001). Multivariable analysis distinguished four independent predictors for OMD: indeterminate lesions on preoperative CT, tumor size > 30 mm, abdominal pain, and preoperative CA 19-9 > 192 U/mL. CONCLUSIONS: Occurrence of OMD in PDAC accounts for 8% of cases. Preoperative CA 19-9 > 192 U/mL, primary tumor size > 30 mm, and identification of indeterminate lesions in preoperative CT may indicate the need for diagnostic laparoscopy.
- Barriers to Surgical Resection of Pancreatic Adenocarcinoma
Annals of surgical oncology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30406483
Preneoplastic and Preinvasive Lesions
Preneoplastic and Preinvasive Lesions, PanIN, IPMN, MCN, ICPN
- Precursor Lesions of Pancreatic Cancer
Oncology research and treatment 2018 09;41(10):603-610
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30269131
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. Although the treatment modalities are improving, the prognosis of PDAC continues to be poor. Therefore, early detection of PDAC or its precursor lesions may be the best way to improve patient survival. PDACs have several different precursor lesions, including pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), intraductal tubulopapillary neoplasms (ITPNs), intraductal oncocytic papillary neoplasms (IOPNs), and mucinous cystic neoplasms (MCNs). PanINs cannot be identified using imaging modalities, while the other lesions are radiologically detectable. These precursor lesions are categorized based on structural and cytological atypia as low-grade and high-grade lesions. We discuss recent updates regarding histopathological and molecular pathological overviews of PDAC precursor lesions. Better understanding of such lesions may contribute to earlier detection of PDAC or its precursor lesions and improve PDAC patient survival.
- Subtyping of intraductal papillary mucinous neoplasms – pitfalls of MUC1 immunohistochemistry
https://onlinelibrary.wiley.com/doi/abs/10.1111/apm.12900
- Cancerization of the Pancreatic Ducts: Demonstration of a Common and Under-recognized Process Using Immunolabeling of Paired Duct Lesions and Invasive Pancreatic Ductal Adenocarcinoma for p53 and Smad4 Expression
https://journals.lww.com/ajsp/Fulltext/2018/11000/Cancerization_of_the_Pancreatic_Ducts_.16.aspx
- Toll-like receptors 2, 4 and 9 and hypoxia markers HIF-1alpha and CAIX in pancreatic intraepithelial neoplasia
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 2018 Nov;126(11):852-863
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30357962
Pancreatic cancer arises from precursor lesions called pancreatic intraepithelial neoplasia (PanIN) characterized by inflammatory microenvironment. In pancreatic cancer, strong innate immunity and hypoxia responses are typical. Occurrence and relationship of these responses in human PanINs is unknown. We have studied the expression of toll-like receptors (TLR) TLR2, TLR4 and TLR9, and hypoxia markers HIF-1alpha and Carbonic anhydrase IX (CAIX) in normal and inflamed pancreatic ducts, in PanINs and in cancers. The samples of 69 surgically resected pancreatic ductal adenocarcinoma patients were stained using immunohistochemistry. We found TLR2, TLR9, HIF-1alpha and CAIX to be prominently expressed in pancreatic intraepithelial neoplasia. Expression of TLR2 showed a linear increase from PanIN1 to PanIN3, while the highest TLR4 expression was detected in inflamed ducts, and TLR9 expression in PanIN1 lesions. Within the PanIN1-group, nuclear HIF-1alpha correlated with membranous and cytoplasmic TLR2 expression (ρ = 0.982 and 0.815; p < 0.001 and p = 0.025, respectively), and in the PanIN2-group nuclear HIF-1alpha correlated with nuclear TLR9 expression 0.636, p = 0.026). Our findings show that the expression of TLRs 2, 4 and 9, and hypoxia markers HIF-1alpha and CAIX is abnormal in pancreatic intraepithelial neoplasia suggesting that both the innate immunity activation and hypoxia response are involved in early pancreatic carcinogenesis. However, these processes might be independent.
- Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features
Gastroenterology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30342036
BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about mechanism of progression. This makes it a challenge to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs; 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. RESULTS: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. CONCLUSIONS: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs-we call these the sequential, branch-off, and de novo subtypes. Subtypes might associate with clinical and pathology features and be used to select surveillance programs for patients with IPMNs.
- Increased SOX9 Expression in Premalignant and Malignant Pancreatic Neoplasms
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30357576
BACKGROUND: SOX9, a progenitor cell marker, is important for pancreatic ductal development. Our goal was to examine SOX9 expression differences in intraductal papillary mucinous neoplasms (IPMNs) and ductal adenocarcinoma (PDAC) compared with benign pancreatic duct (BP). METHODS: SOX9 expression was evaluated by immunohistochemistry performed on 93 specimens: 37 BP, 24 low grade (LG) IPMN, 12 high grade (HG) IPMN, and 20 PDAC. A linear mixed-effects model was used to compare the percentage of cells expressing SOX9 by specimen type. A separate linear mixed-effects model evaluated differences in SOX9 expression by staining intensity in pancreatic epithelial cells. RESULTS: Nuclear SOX9 expression was detected in the epithelial cells of 98% HG IPMN, 93% LG IPMN, 83% PDAC, and 60% BP. Compared with BP, SOX9 was expressed from a significantly greater percentage of cells in LG IMPN, HG IMPN, and PDAC (p < 0.001 for each). BP and PDAC showed greater variability in SOX9 expression in epithelial cells compared with IPMNs which showed strong, homogenous SOX9 expression in almost all cells. Compared with BP, both LG and HG IPMN showed significantly greater SOX9 expression (p < 0.001 for each), but there was no significant difference in SOX9 expression between LG and HG IPMN (p > 0.05). PDAC had significantly higher expression of SOX9 compared with BP but significantly lower SOX9 expression compared with LG or HG IPMN (p < 0.001 for each). CONCLUSIONS: IPMNs demonstrated the highest expression levels of SOX9. SOX9 expression in BP and PDAC demonstrated much more heterogeneity compared with the strong, uniform expression in IPMN.
- Clinical Management and Surgical Decision-Making of IPMN of the Pancreas
https://link.springer.com/protocol/10.1007/978-1-4939-8879-2_2
- The epithelial-mesenchymal transition induces aggressivity of mucinous cystic neoplasm of the pancreas with neuroendocrine component: An immunohistochemistry study
Pathology, research and practice 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30391209
BACKGROUND: Pancreatic mucinous cystic neoplasms (MCN) are rare tumors that are usually diagnosed in females. MATERIALS AND METHODS: In our department, only four of the 109 consecutive cases of pancreatic tumors (3.67%) were diagnosed as MCNs. In this report, we present the characteristics of these four specific cases which also showed unusual HER-2 positivity and neuroendocrine differentiation. RESULTS: The four MCNs were diagnosed in patients with ages between 46 and 75 years. Other clinical particularities were the following: one benign case, splenic rupture as result of a giant cystic tumor on the tail of the pancreas directly invading the spleen in the second one, metastases in the accessory spleen in the third one and invasion of the abdominal vessels in the fourth case. In all of these cases, the ovarian-like stroma tested positivity for calretinin, progesterone receptor (PR) and, in cases 2 and 3, for AE1/AE3 keratin. The malignant tumor cells were marked by carcinoembryonic antigen, HER-2, maspin, PR and the neuroendocrine markers synaptophysin, CD56, and neuron-specific enolase. CONCLUSIONS: These cases highlight the unusually aggressive behavior of pancreatic MCN with invasive carcinomas that share mixed exo- and endocrine components and show epithelial-mesenchymal transition.
- Adjuvant chemotherapy is associated with improved postoperative survival in specific subtypes of invasive intraductal papillary mucinous neoplasms (IPMN) of the pancreas: it is time for randomized controlled data
HPB : the official journal of the International Hepato Pancreato Biliary Association 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30366881
BACKGROUND: Very little is known about adjuvant chemotherapy for invasive Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas. The aim was to assess whether adjuvant chemotherapy affects survival. METHODS: Retrospective evaluation of invasive IPMNs. Patients treated with surgery alone or followed by adjuvant chemotherapy were compared in terms of survival. RESULTS: A total of 102 invasive IPMNs were analyzed. Median follow-up was 72 (5-318) months and 18.6% received adjuvant chemotherapy. Overall, recurrence rate was 40.2%, while 5-year overall survival and disease specific survival (DSS) were 65.3% and 69.4%, respectively. N1 disease (HR5.58, CI95% 2.49-12.51, p < 0.01), tubular type (HR2.35, CI95% 1.71-4.82, p = 0.05) and G3 tumors (HR4.54, CI95% 2.12-15.49, <0.01) were predictors of reduced DSS. Overall, there was no difference in the 5-year DSS comparing patients treated with adjuvant chemotherapy to surgery alone (61.8 vs. 69.4%, p = 0.8). Adjuvant chemotherapy significantly improved DSS only in N1 (5-years-DSS 76 vs. 35.8%, p = 0.01) and tubular carcinomas (5-years-DSS 88.9 vs. 53%, p = 0.03). CONCLUSIONS: Adjuvant therapy improves survival only in invasive IPMNs with nodal disease or tubular differentiation. Future trials are needed to improve the level of evidence about adjuvant chemotherapy.
- High-grade Dysplasia in Resected Main-duct Intraductal Papillary Mucinous Neoplasm (MD-IPMN) is Associated with an Increased Risk of Subsequent Pancreatic Cancer
The American journal of gastroenterology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30413822
BACKGROUND: There is lack of consensus on post-operative surveillance for resected non-invasive intraductal papillary neoplasms (IPMNs). In this study we explored risk factors for subsequent PC in patients with MD-IPMN undergoing partial pancreatectomy. METHODS: We searched the Mayo Clinic surgical pathology database for all cases of resected MD-IPMN between 1997 and 2014. Cases with histologically confirmed main pancreatic duct involvement either isolated or in a mixed pattern with branch-duct involvement were included. Outcomes of PC in the remnant pancreas, and death related to MD-IPMN were assessed with survival analyses (Kaplan-Meier and Cox regression). RESULTS: Among the 179 patients with resected MD-IPMN the incidence of concomitant PC and high-grade dysplasia (HGD) in the resected specimen was 23 and 14%, respectively. The mean duration of follow-up was 4.31 years (range 0.12-13.5 years). Excluding 28 subjects who either underwent initial total pancreatectomy or partial pancreatectomy with surgical margins positive for PC/HGD, the 5-year incidence of subsequent PC was 12%, including 60.6% and15.6% in those with initial PC and HGD, respectively. The 10-year incidence of PC was 21.2% overall, 60.6% for PC, 38.3% for HGD, and 3.0% for LGD. Risk of subsequent PC was significantly higher for those with initial PC compared with HGD (HR = 4.95, 95% CI: 1.63-15.03, p = 0.005 and for HGD compared with LGD (HR = 11.30, 95% CI: 1.55-82.26, p = 0.017). CONCLUSION: Patients with MD-IPMN with PC or HGD undergoing segmental pancreatectomy are at higher risk of subsequent PC and may benefit from post-operative surveillance. The post-operative surveillance intervals in resected MD- IPMNs need to be tailored based on dysplasia grade.
- Adjuvant chemotherapy is associated with improved postoperative survival in specific subtypes of invasive intraductal papillary mucinous neoplasms (IPMN) of the pancreas: it is time for randomized controlled data
https://www.sciencedirect.com/science/article/abs/pii/S1365182X18344630
- Cyst location and presence of high grade dysplasia or invasive cancer in intraductal papillary mucinous neoplasms of the pancreas: a seven institution study from the central pancreas consortium
https://www.sciencedirect.com/science/article/abs/pii/S1365182X1834468X
- Intraductal papillary mucinous neoplasm to pancreas ductal adenocarcinoma sequence and pancreas cancer screening
- Histo-molecular oncogenesis of pancreatic cancer: From precancerous lesions to invasive ductal adenocarcinoma
https://www.wjgnet.com/1948-5204/full/v10/i10/317.htm
- An extremely rare case who underwent total remnant pancreatectomy due to recurrent pancreatic metastasis of intraductal tubulopapillary neoplasm
https://link.springer.com/article/10.1007/s12328-018-0913-x
- Total Pancreatectomy for Presumed Intraductal Papillary Mucinous Neoplasms: A Multicentric Study of the French Surgical Association (AFC)
- Endoscopic Ultrasound Assessment of Pancreatic Duct Diameter Predicts Neuroendocrine Tumors and Other Pancreas Masses
Pancreas 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30451795
OBJECTIVES: Distinguishing neuroendocrine tumors (NETs) and other pancreas lesions from adenocarcinomas via endoscopic ultrasound (EUS) requires additional tissue for special staining and processing. Our aim was to determine if main pancreatic duct (PD) diameter on EUS helps to differentiate NET and other unusual tumors from adenocarcinoma. METHODS: We evaluated 30 consecutive patients diagnosed with NET or other pancreas lesions by EUS with 90 matched patients who were found to have adenocarcinoma. Dilated PD was defined as greater than 3 mm. Multivariate logistic regression was used to evaluate associations between lesion type and PD diameter. RESULTS: Among the 30 patients with NET/other pancreas lesions, 21 had NETs, 7 had metastases, and 2 had lymphomas. A dilated PD was demonstrated in only 3.3% of pancreatic NET/other lesions but present in 88.9% of cases of primary adenocarcinoma (P < 0.01). In multivariate analysis, a normal PD diameter and absence of clinical symptoms strongly predicted the presence of pancreatic NET/other versus adenocarcinoma (P < 0.01). CONCLUSIONS: The absence of PD dilation upstream of the lesion suggests NET or other lesions rather than adenocarcinoma. This finding should prompt endosonographers to obtain additional tissue at the time of EUS to send for special studies.
- Cystic tumors of the pancreas. An update of the surgical experience in a single institution
https://online.reed.es/DOI/PDF/ArticuloDOI_5798.pdf
- Concomitant Intraductal Papillary Mucinous Neoplasm in Pancreatic Ductal Adenocarcinoma Is an Independent Predictive Factor for the Occurrence of New Cancer in the Remnant Pancreas
Annals of surgery 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30308608
OBJECTIVE: To determine the factors predicting the subsequent development of pancreatic ductal adenocarcinoma in remnant pancreas (PDAC-RP) after partial pancreatectomy for PDAC. SUMMARY BACKGROUND DATA: PDAC-RP after partial pancreatectomy for PDAC is currently not so rare because of improved prognosis of PDAC patients due to recent advances in surgical techniques and adjuvant therapy. However, the predictive factors related to PDAC-RP remain unknown. METHODS: We retrospectively reviewed the clinicopathological data of a consecutive series of 379 patients with PDAC treated by partial pancreatectomy between 1992 and 2015; 14 patients (3.69%) had PDAC-RP. Clinicopathological variables were compared between PDAC-RP and non-PDAC-RP. RESULTS: In univariate analysis, concomitant intraductal papillary mucinous neoplasm (IPMN) (P = 0.0005), cancer location (body/tail) (P = 0.0060), and lower T factor in UICC (P = 0.0039) were correlated with PDAC-RP development. Multivariate analysis revealed concomitant IPMN (P = 0.0135) to be an independent predictive factor for PDAC-RP. PDAC concomitant with IPMN had higher cumulative incidence of PDAC-RP (47.5%/10 yrs) than PDAC without IPMN (9.96%/10 yrs) (P = 0.0071). Moreover, the density of pancreatic intraepithelial neoplasia lesions in the background pancreas of cases of PDAC concomitant with IPMN (1.86/cm) was higher than that of cases of PDAC without IPMN (0.91/cm) (P = 0.0007). CONCLUSIONS: Concomitant IPMN in PDAC is an independent predictive factor for the development of new PDAC in remnant pancreas. Cancer susceptibility of remnant pancreas after resection for PDAC concomitant with IPMN is probably due to an increased density of pancreatic intraepithelial neoplasia lesions.
- Pancreatic Cysts Sinister Findings or Incidentalomas?
https://www.medical.theclinics.com/article/S0025-7125(18)30095-6/fulltext
Microenvironment
Tumor Stroma Interactions, Microenvironment, Inflammatory Response, Epithelial Mesenchymal Transition
- Tumor-Infiltrating NETs Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30374923
BACKGROUND: Tumor-infiltrating neutrophils (TINs) indicate poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). Activated neutrophils can generate neutrophil extracellular traps (NETs). Little is known about the presence and prognostic significance of tumor-infiltrating NETs in PDAC. METHODS: This study enrolled 317 patients, in two independent sets (training and validation), who underwent curative pancreatectomy for PDAC in Shanghai Cancer Center. TINs and NETs were identified by immunohistochemical staining for CD15 and citrullinated histone H3, respectively. The relationship between clinicopathological features and outcomes was analyzed. Accuracy of prognostic prediction models was evaluated using concordance index (C-index) and Akaike information criterion (AIC). RESULTS: NETs were associated with OS (both, P < 0.001) and RFS (both, P < 0.001) in the training and validation sets. Tumor-infiltrating NETs predicted poor postsurgical survival of patients with PDAC. Moreover, multivariate analysis identified NETs and AJCC TNM stage as two independent prognostic factors for OS and RFS. Combination of NETs with the 8th edition TNM staging system (C-index, 0.6994 and 0.6669, respectively; AIC, 1067 and 1126, respectively) generated a novel model that improved the predictive accuracy for survival in both sets (C-index, 0.7254 and 0.7117, respectively; AIC, 1047 and 1102, respectively). The model combining presence of NETs with the 7th edition AJCC TNM staging system also had improved predictive accuracy. CONCLUSIONS: NETs were an independent prognostic factor in PDAC and incorporation of NETs along with the standard TNM stating system refined risk-stratification and predicted survival in PDAC with improved accuracy.
- Mesenchymal-epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells
Pathology international 2018 Apr;68(4):214-223
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29457853
Epithelial-mesenchymal transition (EMT) promotes invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the importance of its reverse process, mesenchymal-epithelial transition (MET), for PDAC remains unclear. We aimed to characterize the histological finding “focal differentiation” in PDAC at perineural invasion sites in the context of MET and to investigate the role of Schwann cells in inducing tumor MET. Tumor differentiation and immunohistochemical expressions of E-cadherin, SMAD3, and vimentin at perineural invasion sites were examined in 168 PDAC tissues. Four PDAC cell lines were co-cultured with Schwann cells to investigate cell morphology, motility, or EMT-related markers using immunocytochemistry and quantitative PCR. Of 168 tumors, 124 (74%) showed focal differentiation with enhanced E-cadherin membrane expression (P < 0.001) and decreased nuclear accumulation of SMAD3 (P < 0.001). Among 115 PDACs harboring grade 1/2 tumor, tumors with focal differentiation showed worse survival compared to those without focal differentiation (P = 0.019). PDAC cells co-cultured with Schwann cells demonstrated a sheet-like appearance, increased E-cadherin expression, decreased expressions of SMAD3 and vimentin, and reduced cell motility. In conclusion, MET-like change is induced by Schwann cells, suggesting that Schwann cells contribute to PDAC colonization in pancreatic nerves through activating the MET machinery inside tumor cells in the pancreatic tumor microenvironment.
- Expression of Epithelial-Mesenchymal Transition Proteins in Pancreatic Anaplastic (Undifferentiated) Carcinoma
Pancreas 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30451796
OBJECTIVES: The aim of this study was to identify an association of pancreatic anaplastic carcinoma (APC) with the epithelial-mesenchymal transition (EMT). METHODS: Resected APCs (n = 24) were examined to assess components of APCs, including carcinomatous, transitional, and sarcomatous regions. Analysis was performed based on the immunoreactivity of E-cadherin and 3 EMT-related proteins: Slug (zinc finger protein SNAI2), Twist (Twist-related protein 1), and Zeb1 (zinc finger E-box-binding homeobox 1). Expression score was determined based on staining intensity and stained area of the target cells. Finally, we performed a hierarchical clustering based on the expression pattern of E-cadherin and EMT-related proteins of the sarcomatous component. RESULTS: The expression score of E-cadherin decreased in the order of sarcomatous > transitional > carcinomatous components (P < 0.01). Although there were significant differences in the immunohistochemical scores of Slug, Twist, and Zeb1 between carcinomatous and transitional components (P < 0.01), the significant difference in immunohistochemical score of Zeb1 between transitional and sarcomatous components was found (P < 0.05). Furthermore, APCs were divided into 2 subgroups based on the expression patterns of E-cadherin and EMT-related proteins (hierarchical clustering analysis). Consequently, these subgroups were distinguished by Twist expression. CONCLUSIONS: Epithelial-mesenchymal transition plays an essential role in the pathogenesis of APC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
- Tenascin C, Fibronectin, and Tumor-Stroma Ratio in Pancreatic Ductal Adenocarcinoma
Pancreas 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30451798
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma with increased expression of tenascin C and fibronectin. Their role and tumor-stroma ratio in PDAC are not well known. The aim of this study was to evaluate tenascin C and fibronectin expression and tumor-stroma ratio and their prognostic relevance in PDAC. METHODS: Ninety-five resected PDACs were immunohistochemically stained for tenascin C and fibronectin, and the expression was separately assessed in tumor bulk and front. Tumor-stroma ratio was determined with sections stained with hematoxylin-eosin. RESULTS: Tenascin C and fibronectin were abundantly expressed in the stroma of PDAC, but absent in adjacent normal pancreatic tissue. Fibronectin expression of the bulk was associated with high T class (P = 0.045). In the main analysis, tenascin C and fibronectin expression and tumor-stroma ratio were not associated with patient survival. In a subgroup analysis of early-stage PDAC (T1-T2 tumors), high tenascin C expression in the tumor bulk was associated with poor prognosis (hazard ratio, 8.23; 95% confidence interval, 2.71-24.96). CONCLUSIONS: Tenascin C and fibronectin are abundantly expressed in PDAC, but they seem to have no major association with patient survival. However, in early-stage PDAC, tenascin C expression of the tumor bulk may have prognostic impact. Tumor-stroma ratio has no prognostic value in PDAC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
- PD-L1 expression in pancreatic adenosquamous carcinoma: PD-L1 expression is limited to the squamous component
https://www.sciencedirect.com/science/article/pii/S0344033818307076
- Current approaches to immunotherapy in noncolorectal gastrointestinal malignancies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173942/
- Epithelial-Stromal Interactions in Pancreatic Cancer
https://www.annualreviews.org/doi/abs/10.1146/annurev-physiol-020518-114515
- Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer
Gut 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30415234
OBJECTIVE: Pancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer. DESIGN: We performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy. RESULTS: We identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment. CONCLUSIONS: Our data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.
- Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3β/Snail signaling
https://www.nature.com/articles/s41388-018-0392-z
- Neoepitope targets of tumour-infiltrating lymphocytes from patients with pancreatic cancer
https://www.nature.com/articles/s41416-018-0262-z
- Typing of pancreatic cancer-associated fibroblasts identifies different subpopulations
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224473/
- Pancreatic Cancer Subtypes: Beyond Lumping and Splitting
https://www.gastrojournal.org/article/S0016-5085(18)35213-2/pdf
https://www.ncbi.nlm.nih.gov/pubmed/30419209
- Hyperglycemia aggravates microenvironment hypoxia and promotes the metastatic ability of pancreatic cancer
Computational and structural biotechnology journal 2018 10;16():479-487
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30455857
Background: Diabetes mellitus and pancreatic cancer are intimately related. Our previous studies showed that high levels of blood glucose promote epithelial-mesenchymal transition of pancreatic cancer. In this study, we evaluated the relationship between hyperglycemia and hypoxic tumor microenvironments. Methods: HIF-1α expression was evaluated by immunohistochemistry in clinical pancreatic cancer tissues with or without diabetes mellitus. Statistcal analysis was performed to explore the relationship between HIF-1α expression and pathological features of patients with pancreatic cancer. In vivo and in vitro models was established to detect whether a hyperglycemia environment could cause hypoxia in the pancreatic parenchyma and promote pancreatic cancer. In addition, we also tested the effect of HIF-1α siRNA on the high glucose-induced invasive and migratory abilities of BxPC-3 cells in culture. Result: Our data showed that pancreatic cancer patients with diabetes had a higher level of HIF-1α expression as well as biliary duct invasion and larger tumor volumes than individuals in the euglycemic group. Diabetic nude mice treated with streptozotocin (STZ) exhibited larger tumors and were more likely to develop liver metastasis than control mice. Acinar cells of the pancreas in diabetic mice showed an obvious expansion of the endoplasmic reticulum and increased nuclear gaps as well as chromatin close to the cellular membrane in some acinar cells. The expression area for Hypoxyprobe-1 and HIF-1α in the diabetic orthotopic xenograft group was larger than that in the control group. The expression level of HIF-1α in the BxPC-3 cancer cell line increased in response to high glucose and CoCl2 concentrations. The high glucose-induced invasive ability, migratory capacity and MMP-9 expression were counter-balanced by siRNA specific to HIF-1α. Conclusion: Our results demonstrate that the association between hyperglycemia and poor prognosis can be attributed to microenvironment hypoxia in pancreatic cancer.
- Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness
https://www.sciencedirect.com/science/article/pii/S0142961218308007
- CMV and EBV targets recognized by tumor-infiltrating B lymphocytes in pancreatic cancer and brain tumors
https://www.nature.com/articles/s41598-018-34710-2
- Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going
Experimental & molecular medicine 2017 12;49(12):e406
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29611542
Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.
- Elucidating the link between collagen and pancreatic cancer: what’s next?
Expert review of gastroenterology & hepatology 2018 04;12(4):315-317
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29495889
- Features of Immune Cells and the Tumor-Associated Stroma Tango as Prognostic Factors in Patients With Pancreatic Ductal Adenocarcinoma
Gastroenterology 2018 11;155(5):1312-1314
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30300611
- Osthole inhibits pancreatic cancer progression by directly exerting negative effects on cancer cells and attenuating tumor-infiltrating M2 macrophages
Journal of pharmacological sciences 2018 Jul;137(3):290-298
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30098910
Pancreatic cancer has remained a major cause of cancer-related deaths. A hallmark of pancreatic cancer is extensive stromal reactions, resulting in a unique tumor microenvironment, especially the involvement of macrophages. These tumor-educated cells limit the efficacy of chemotherapy. Therefore, it is necessary to identify an effective treatment strategy. In this study, we aimed to explore the anti-tumor and immunomodulatory effects of osthole on pancreatic cancer. We found that osthole suppressed Panc 02 cell migration and proliferation and induced apoptosis as shown in vitro. Osthole also attenuated the development of pancreatic cancer in mice by inhibiting tumor-infiltrating M2 macrophages in our study. Additionally, osthole inhibited the polarization of primary bone marrow cells into M2 macrophages and inhibited the expression of MRC1, CCL22 and TGF-β in the M2 polarization process in vitro. Detection of the related signaling pathways revealed that osthole exerted immunomodulatory effects on M2 macrophages by down-regulating p-STAT6 and the p-ERK1/2-C/EBP β axis. These results indicated that osthole has effective anti-tumor and immunomodulatory effects on pancreatic cancer.
- ASO Author Reflections: Regulation of Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma by Vitamin D Supplementation
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30324470
- Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma
http://stm.sciencemag.org/content/10/464/eaat3487
SPN
Solid Pseudopapillary Neoplasm
- CD138/syndecan-1 in pancreatic solid and pseudopapillary neoplasms
Journal of clinical pathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30275097
- Solid Pseudopapillary Neoplasm of the Pancreas in a Young Pediatric Patient: A Case Report and Systematic Review of the Literature
Pancreas 2018 10;47(10):1364-1368
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30325866
Solid pseudopapillary neoplasms (SPNs) are the most common pediatric pancreatic tumor; however, most data in children are extrapolated from adults. This study describes a young presentation of SPN in a 5-year-old girl and presents a comprehensive systematic review of the literature regarding SPNs in children. A systematic review was performed using PubMed and Embase for all articles in English using predetermined search terms, including “solid pseudopapillary neoplasm” and “pediatric” and historical terms for SPN. A total of 523 pediatric patients were identified in 135 articles. Eighty-three percent of patients were female, and median age was 13.6 years. Abdominal pain was the most frequent presenting symptom (78%), and median tumor size was 8.2 cm. The pancreatic head was involved in 46% of cases. Computed tomographic scan was the most common imaging modality (87%), and 61% were diagnosed by fine needle aspiration. Surgical resection was reported in 507 patients, with a complication rate of 21.1% reported in 393 patients. Only 3.8% received adjuvant therapy, and 6.7% had recurrent disease. Solid pseudopapillary neoplasms of the pancreas are rare tumors in childhood. Male sex and pancreatic head involvement are seen more often in children than in adults. Surgery remains the mainstay of treatment with excellent results.
Solid Pseudopapillary Neoplasm of the Pancreas in a Young Pediatric Patient: A Case Report and Systematic Review of the Literature.
- Solid Pseudopapillary Neoplasm of the Pancreas in a Young Pediatric Patient: A Case Report and Systematic Review of the Literature.
https://www.ncbi.nlm.nih.gov/pubmed/30325866
- Clinicopathologic features of solid pseudopapillary pancreatic neoplasms in an Eastern Caribbean population
Tropical doctor 2018 Jul;48(3):224-227
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29198177
Pancreatic solid pseudopapillary neoplasms (SPNs) are uncommon lesions across the globe. Their incidence is unknown in the Caribbean. This retrospective study sought to document the clinicopathologic features of pancreatic SPNs in an Eastern Caribbean population. We examined data from the hospital records of all patients with SPN in Trinidad and Tobago, finding 11 cases over five years, equating to an incidence of 0.17 cases per 100,000 population per year. The lesions occurred in girls and young women at a mean age of 25 years, with a propensity for those of Afro-Caribbean descent. Poor prognostic factors (histologic invasion of the capsule, lymphovascular invasion, spindle cells, anaplastic cells and/or excessive mitotic figures) were present in 82% at the time of diagnosis. These tumours are uncommon in our population, and since most have poor prognostic features at diagnosis, we advocate an aggressive surgical approach.
SCA
- Serous cystadenoma of pancreas: A clinicopathologic experience of 23 cases from a major tertiary care center
https://journals.sagepub.com/doi/pdf/10.1177/2036361318809183
Pancreatitis & Other Diseases
- Morphologic Overlap Between Inflammatory Myofibroblastic Tumor and IgG4-related Disease Lessons From Next-generation Sequencing
- Prior History of Pancreatitis Accelerates the Development of Pancreatic Adenocarcinoma
Pancreas 2019 11;47(10):1262-1266
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30286010
OBJECTIVES: Presentation of pancreatic adenocarcinoma (PC) as acute pancreatitis (AP), association of chronic pancreatitis (CP) with PC, and role of inflammation in PC carcinogenesis are well recognized. We hypothesized that inflammatory changes associated with remote history of AP (≥2 years before PC diagnosis) would result in earlier age of PC diagnosis. METHODS: We evaluated PC patients prospectively enrolled in the Pancreatic Adenocarcinoma Gene Environment Risk (PAGER) study at the University of Pittsburgh for history of pancreatitis and reviewed relevant medical records and imaging studies. Univariate and multivariable linear regression analyses evaluated the relationship between PC and remote history of AP. RESULTS: Among 790 patients with histologically confirmed PC, 114 (14.4%) had a history of pancreatitis (AP within 2 years of PC diagnosis in 69 [8.7%], remote history of AP in 28 [3.5%], CP in 4 [0.5%], and unknown duration of pancreatitis in 13 [1.6%]). After controlling for age, sex, body mass index, smoking, alcohol history, and diabetic status at diagnosis, patients with a remote history of AP were diagnosed on average 4.7 years earlier with PC when compared with PC patients without history of AP (P < 0.035). CONCLUSIONS: Remote history of AP may accelerate carcinogenesis in PC.
- Management of pregnancy-associated pancreatic cystic tumors: Review of the literature and results of a Pancreas Club Inc. Survey
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;18(8):905-912
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30274883
BACKGROUND/OBJECTIVES: Management of patients with pregnancy-associated cyst pancreatic cystic tumors (PA-PCT) is complicated by lack of large series. METHODS: A systematic literature review was conducted to extrapolate data on management of PA-PCT, and make a questionnaire on pending issues to be administered to the members of the Pancreas Club Inc. RESULTS: The literature review demonstrated a total of 35 PA-PCT in 34 women, described exclusively in the form of case reports, and permitted the identification of eleven key questions to be addressed in the survey. The combined analysis of literature review and survery responses provided several information. First, PA-PCT are predominantly located in the body-tail of the pancreas, cause non-specific symptoms, are of large size (mean size: 11.2 ± 4.5 cm), and are nearly always malignant or premalignant, making timing of surgery, and not indication for surgery, the main issue in the management of these tumors. Second, there is a risk of PA-PCT rupture during pregnancy. Ruptured PA-PCT had a mean size 13.5 ± 4.9 cm, but no prognostic factor could be identified. Survey opinions suggested that this occurrence is quite rare, even for large tumors. Third, most pregnancies were conducted to term (mean gestational age: 40.5 ± 0.7 weeks), with a vaginal delivery. Fourth, all procedures were carried out through an open approach and the spleen was rarely preserved. Survey indicated instead that laparoscopy could play a role, and that the spleen should be preserved when feasible. CONCLUSIONS: PA-PCT require individualized treatment. The definition of a management algorithm requires the implementation of an International Registry.
- Pancreatic mass and subcutaneous nodules
Gastroenterology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30296438
- Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation
Journal of clinical research in pediatric endocrinology 2018 06;10(2):168-174
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28943513
Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the pancreas-specific transcription factor 1A (PTF1A) enhancer and one with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, due to a KCNJ11 mutation. The two cases with mutations in the distal enhancer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analyses showed that these mutations can decrease expression of PTF1A which is involved in pancreas development. Both patients were born small for gestational age to consanguineous parents. Both were treated with insulin and pancreatic enzymes. One of these patients’ fathers was also homozygous for the PTF1A mutation, whilst his partner and the parents of the other patient were heterozygous carriers. In the case with DEND sydrome, a previosly reported heterozygous KCNJ11 mutation, p.Cys166Tyr (c.497G>A), was identified. This patient was born to nonconsanguineous parents with normal birth weight. The majority of neonatal diabetes patients with KCNJ11 mutations will respond to sulphonylurea treatment. Therefore Glibenclamide, an oral antidiabetic of the sulphonylurea group, was started. This treatment regimen relatively improved blood glucose levels and neurological symptoms in the short term. Because we could not follow the patient in the long term, we are not able to draw conclusions about the efficacy of the treatment. Although neonatal diabetes mellitus can be diagnosed clinically, genetic analysis is important since it is a guide for the treatment and for prognosis.
- Foreign body: A sewing needle migrating from the gastrointestinal tract to pancreas
Turkish journal of surgery 2018 01;34(3):256-258
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30302435
Of all ingested foreign bodies, 2.4% comprise of sewing needles. Through perforation of gastrointestinal tract, which occurs in 1% of cases, they can migrate into the liver and pancreas. Foreign bodies in pancreas should be considered in the differential diagnosis of chronic abdominal pain. Computed tomography scans provide valuable information for the localization of the lesion, which guide the surgeon during the operation. Secondary to foreign bodies that migrate to the pancreas, complications with high mortality such as pancreatitis, pseudoaneurysm, and pancreas abscess can be seen. Thus, for this patient group, diagnostic laparoscopy is recommended, considering its advantages of decreased postoperative pain, decreased wound infection, and faster recovery time. Here we present a case of a 23-year-old female patient, from whom an ingested needle that migrated from the back wall of the stomach to the pancreas was extracted by laparoscopic surgery.
- The National Trends in Acute and Chronic Pancreatitis Needs to Be Improved
Gastroenterology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315779
- Pancreatic Cancer Following Acute Pancreatitis: A Population-based Matched Cohort Study
The American journal of gastroenterology 2018 Nov;113(11):1711-1719
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315287
BACKGROUND: Acute pancreatitis is linked to pancreatic cancer, but the direction of this association is not fully elaborated. METHODS: This was a population-based cohort study including all Swedish residents diagnosed with a first-time episode of acute pancreatitis between 1997 and 2013 and corresponding matched pancreatitis-free individuals from the general population. Hazard ratios for the association between acute pancreatitis and pancreatic cancer were estimated using multivariable Cox regression models. RESULTS: Overall, 49,749 individuals with acute pancreatitis and 138,750 matched individuals without acute pancreatitis were followed up for 1,192,134 person-years (median 5.3 years). A total of 769 individuals developed pancreatic cancer, of whom 536 (69.7%) had a history of acute pancreatitis. The risk of pancreatic cancer was substantially increased during the first few years after a diagnosis of acute pancreatitis but declined gradually over time, reaching a level comparable to the pancreatitis-free population after >10 years of follow-up. In those with non-gallstone-related acute pancreatitis, the risk of pancreatic cancer declined to a level comparable to the pancreatitis-free population only when follow-up time was censored for a second episode of acute pancreatitis or a diagnosis of chronic pancreatitis. Increasing number of recurrent episodes of acute pancreatitis was associated with increased risk of pancreatic cancer. CONCLUSION: These findings imply a delay in the diagnosis of pre-existing pancreatic cancer, if clinically presented as acute pancreatitis. Any association between non-gallstone-related acute pancreatitis and pancreatic cancer in the long-term (>10 years) could be mediated through recurrent acute pancreatitis or chronic pancreatitis.
- Serum and histological IgG4-negative type 1 autoimmune pancreatitis
http://link-springer-com-443.webvpn.jxutcm.edu.cn/article/10.1007%2Fs12328-018-0919-4
- The histologic diagnosis of IgG4‐related disease on small biopsies: Challenges and pitfalls
https://onlinelibrary.wiley.com/doi/abs/10.1111/his.13787
- Coexisting Mucinous Cystic Neoplasm of the Pancreas and Type 1 Autoimmune Pancreatitis
https://www.jpatholtm.org/upload/pdf/jptm-2018-10-25.pdf
- Autoimmune pancreatitis in children: A single centre experience in diagnosis, management and long term follow up
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30455055
OBJECTIVES: Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis and data is limited in the paediatric population. We aim to describe in detail a cohort of paediatric patients with AIP including their presentation, investigations that led to their diagnosis, management and long-term follow up. METHODS: We retrospectively reviewed the data of 6 patients diagnosed with AIP over an 10-year period. Data including demographics, clinical information, laboratory parameters, serological markers, radiological and histological findings as well as longitudinal follow up were collected. RESULTS: Out of the six patients, one was diagnosed with definitive Type 1 AIP, two with definitive Type 2 AIP, two with probable Type 2 AIP and one with suspected Type 2 AIP. Median time of follow up was 3.9 years (range 2.6-10.1). 4 patients had pancreatic biopsies with 2 of these patients showing granulocytic epithelial lesions (GELs). 4 patients received steroids and two of them developed ulcerative colitis. Azathioprine was commenced on the patient with Type 1 AIP to help her wean off steroids that caused significant side effects on her. Only two patients developed exocrine insufficiency. CONCLUSIONS: The long term follow up of our cohort of paediatric AIP shows good prognosis. More follow up data on patients with AIP is needed to help further characterize and define the disease.
Techniques & Research Methods
- Understanding Pancreatic Diseases Using Animated Pancreas Patient: Informing Patients for Better Health Outcomes With Visual Formats of Learning
Pancreas 2018 10;47(10):1256-1261
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30286013
OBJECTIVES: The aim of this study was to evaluate the impact of Animated Pancreas Patient (APP) educational modules (APP website and YouTube) on pancreas education, awareness, and health outcomes. METHODS: This was a retrospective study of APP metrics data from September 2013 to October 2017. We evaluated audience reach (number of visit sessions, unique visitors, page views) and calculated top views by media type (animation, expert video, patient video, and slide show) and top retention videos from the modules. We also assessed the educational impact through learner feedback survey. RESULTS: The APP had 1,475,252 views (547,693 unique visitors, 63.1% in United States) during the study period. Most popular topic viewed among the animations was “Role and Anatomy of the Pancreas” (n = 361,116), and most common expert video viewed was “Chronic Pancreatitis: What Foods and Beverages Should I Avoid?” (n = 31,667). Participants who completed the online feedback survey reported knowledge gains and commitments to change. CONCLUSIONS: Pancreas education in visual formats of learning provided by APP demonstrated wide reach and has substantial potential to inform and impact behaviors of patients and caregivers. Continued efforts should be made to provide patient resources that address health literacy and patient education and respond to patient needs for better quality of life and improved health outcomes in pancreatic diseases.
- ASO Author Reflections: Fluorescent-Guided Surgery to Augment Pancreatic Cancer Surgery
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315384
- Subtyping of IPMN
https://link.springer.com/protocol/10.1007/978-1-4939-8879-2_1
- Generation of Induced Pluripotent Stem Cell-Like Lines from Human Pancreatic Ductal Adenocarcinoma
https://link.springer.com/protocol/10.1007/978-1-4939-8879-2_4
- Generation and Culture of Human Pancreatic Ductal Adenocarcinoma Organoids from Resected Tumor Specimens
https://link.springer.com/protocol/10.1007/978-1-4939-8879-2_9
- Spheroid Culture of Human Pancreatic Ductal Cells to Reconstitute Development of Pancreatic Intraepithelial Neoplasia
https://link.springer.com/protocol/10.1007/978-1-4939-8879-2_6
- Generation and Culture of Tumor and Metastatic Organoids from Murine Models of Pancreatic Ductal Adenocarcinoma
https://link.springer.com/protocol/10.1007/978-1-4939-8879-2_10
- An In Vitro Three-Dimensional Organotypic Model to Analyze Peripancreatic Fat Invasion in Pancreatic Cancer: A Culture System Based on Collagen Gel Embedding
https://link.springer.com/protocol/10.1007/978-1-4939-8879-2_11
- Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer
Pancreas 2019 11;47(10):1213-1221
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30325860
High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.
- A “Clearer” View of Pancreatic Pathology: A Review of Tissue Clearing and Advanced Microscopy Techniques.
https://europepmc.org/abstract/med/30256228
- Needle-based confocal laser endomicroscopy of pancreatic cystic lesions: a prospective multicenter validation study in patients with definite diagnosis
https://www.thieme-connect.com/products/ejournals/html/10.1055/a-0732-5356
- Histopathologic Analysis of Pancreaticoduodenectomy Specimen
JNMA; journal of the Nepal Medical Association 2016 12;55(204):79-85
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28029673
INTRODUCTION: Whipple’s Pancreaticoduodenectomy has increasingly been used as an appropriate resectional procedure for tumors of the periampullary region which are pancreatic, periampullary, ampullary and biliary tumors. Our aim was to study the distribution and histopathologic features of these tumors and to examine local trends of periampullary neoplasms resected with a PD. METHODS: A descriptive study was conducted in the department of Pathology, Kathmandu Medical College Teaching Hospital from July 2013 to June 2016. RESULTS: Thirty five patients underwent Whipple’s Pancreaticoduodenectomy procedure during a period of 36 months from July 2013 to June 2016. Malignant tumor was present in 31 (88.57%) cases where as four cases (11.43%) harboured benign lesions. Periampullary mixed carcinoma was the predominant tumor (34.28%) followed by periampullary duodenal (20%), ampullary (14.28%), pancreatic adenocarcinoma (11.42%) and distal cholangiocarcinoma (5.71%). There was no significant difference in tumor size among periampullary, ampullary, pancreatic and biliary carcinomas. Ampullary carcinomas were predominantly well differentiated (80%) where as the other tumors were mostly moderately differentiated. Lymphovascular and perineural invasion varied in different tumor types. Four pancreatic adenocarcinomas showed lymphovascular and perineural invasion. Adequate surgical margin clearance was achieved in most of the cases except in one case each of periampullary duodenal carcinoma and distal cholangiocarcinoma and two cases of pancreatic adenocarcinoma.. CONCLUSIONS: Pancreaticoduodenectomy specimen requires thorough histopathological evaluation. Pathologists should also be aware of possibility of a benign diagnosis in PD specimens which have been resected presuming malignancy based on clinical judgement and radiological data.
Reviews, Opinion Articles
- Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer: From Concept to Reality
Pancreas 2019 11;47(10):1208-1212
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30325859
Research progress in diseases of the exocrine pancreas [chronic pancreatitis (CP), pancreatogenic diabetes mellitus, and pancreatic cancer] has been hampered by the disorders’ heterogeneity, the limitations of previous small cross-sectional studies, the inability to safely obtain pancreatic tissue for study, and the lack of structured epidemiology tools, genetic testing, and biomarker development. Mechanism-based research of these diseases has suffered from the lack of systematically collected clinical measures in longitudinal cohort studies linked with biospecimens. Given the increasing incidence and prevalence of CP and its association to the development of pancreatic cancer, its complications, high mortality rate, and associated health care cost, the National Institute for Diabetes and Digestive and Kidney Diseases and the National Cancer Institute funded the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer to identify research gaps and foster multidisciplinary collaborations to better diagnose, characterize, and manage CP and its sequelae. The CPDPC structure, governance, and research objectives are described in this article. Studies undertaken by the CPDPC are described in other articles in this journal’s issue.
- The Agenda for Accelerating Pancreatic Research
Pancreas 2019 11;47(10):1177-1179
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30325854
- 2018 American Pancreatic Association Presidential Address: Grateful Reflections
Pancreas 2018 10;47(10):1173-1174
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30325852
- Intercepting Pancreatic Cancer: Our Dream Team’s Resolve to Stop Pancreatic Cancer
Pancreas 2019 11;47(10):1175-1176
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30325853
- Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer
https://www.nature.com/articles/s41416-018-0298-0
- The Intricate Metabolism of Pancreatic Cancers
Advances in experimental medicine and biology 2018 6;1063():73-81
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29946776
Currently, approximately 95% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), which is the most aggressive form and the fourth leading cause of cancer death with extremely poor prognosis [1]. Poor prognosis is primarily attributed to the late diagnosis of the disease when patients are no longer candidates for surgical resection [2]. Cancer cells are dependent on the oncogenes that allow them to proliferate limitlessly. Thus, targeting the expression of known oncogenes in pancreatic cancer has been shown to lead to more effective treatment [3]. This chapter will discuss the complexity of metabolic features in pancreatic cancers. To be able to fully comprehend the heterogeneous nature of cancer metabolism, we need to take into account the close relationship between cancer metabolism and genetics. Gene expression varies tremendously, not only among different types of cancers, but also within the same type of cancer among different patients. Cancer metabolism heterogeneity is often prompted and perpetuated not only by genetic mutations in oncogenes and tumor suppressor genes but also by the innate diversity of the tumor microenvironment. Much effort has been focused on elucidating the genetic alterations that correlate with disease progression and treatment response [4]. However, the precise mechanism by which tumor metabolism contributes to cancer growth, survival, mobility, and aggressiveness represents a functional readout of tumor progression.
- ASO Author Reflections: Do Distinct Patterns of Recurrence Impact the Prognosis of Patients With Resected Pancreatic Ductal Adenocarcinoma?
https://link.springer.com/article/10.1245/s10434-018-6820-z
- ASO Author Reflections: Distal Pancreatectomy with Celiac Axis Resection for Locally Advanced Pancreatic Cancer-Patient Selection and Surgical Experience are Key
Annals of surgical oncology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30456669
- ASO Author Reflections: Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma
Annals of surgical oncology 2018 Dec;25(13):3994-3995
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315385
- ASO Author Reflections: Improving Identification of Intraductal Papillary Mucinous Neoplasm Patients at Risk-Current Status and the Role of IPMN Molecular Biomarkers
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30311163
- ASO Author Reflections: Progression after Resection of Noninvasive or Microinvasive Intraductal Papillary Mucinous Neoplasms
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30324467
- Current Therapeutic Options for Pancreatic Ductal Adenocarcinoma
Oncology research and treatment 2018 09;41(10):590-594
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30286472
Pancreatic cancer remains the fourth most common cause of cancer-related mortality and is a major health threat. The majority of cases are diagnosed at advanced disease stages, limiting the chances of long-term survival. Several new therapeutic regimens have been introduced into routine clinical practice in recent years and a plethora of novel approaches is currently undergoing preclinical and early clinical evaluation. This review discusses the current standards of care for systemic therapy of pancreatic cancer and gives a brief outlook on ongoing clinical trials.
- ASO Author Reflections: Do Distinct Patterns of Recurrence Impact the Prognosis of Patients With Resected Pancreatic Ductal Adenocarcinoma?
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30298312
- Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?
World journal of gastroenterology 2018 May;24(20):2137-2151
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29853732
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, mostly due to its resistance to treatment. Of these, checkpoint inhibitors (CPI) are inefficient when used as monotherapy, except in the case of a rare subset of tumors harboring microsatellite instability (< 2%). This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC. The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancer-associated-fibroblast activation and transforming growth factor β secretion. Several strategies have recently been developed to overcome this immunosuppressive microenvironment. Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells. Ongoing studies are therefore exploring the association of CPI with vaccines, oncolytic viruses, MEK inhibitors, cytokine inhibitors, and hypoxia- and stroma-targeting agents. Adoptive T-cell transfer is also under investigation. Moreover, translational studies on tumor tissue and blood, prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.
- Emerging trends in the immunotherapy of pancreatic cancer
Cancer letters 2018 03;417():35-46
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29242097
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the U.S., claiming approximately 43,000 lives every year. Much like other solid tumors, PC evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive tumor microenvironment (TME). Therefore, targeting and reinstating the patient’s immune system could serve as a powerful therapeutic tool. Indeed, immunotherapy has emerged in recent years as a potential adjunct treatment for solid tumors including PC. Immunotherapy modulates the host’s immune response to tumor-associated antigens (TAAs), eradicates cancer cells by reducing host tolerance to TAAs and provides both short- and long-term protection against the disease. Passive immunotherapies like monoclonal antibodies or engineered T-cell based therapies directly target tumor cells by recognizing TAAs. Active immunotherapies, like cancer vaccines, on the other hand elicit a long-lasting immune response via activation of the patient’s immune cells against cancer cells. Several immunotherapy strategies have been tested for anti-tumor responses alone and in combination with standard care in multiple preclinical and clinical studies. In this review, we discuss various immunotherapy strategies used currently and their efficacy in abrogating self-antigen tolerance and immunosuppression, as well as their ability to eradicate PC.
Oncology and serum marker studies
- Clinicopathological characteristics of pancreatic cancer with normal level of serum CA19-9
- Biomarker panel predicts survival after resection in pancreatic ductal adenocarcinoma: A multi-institutional cohort study
https://www.ejso.com/article/S0748-7983(18)31450-1/fulltext
Epidemiology, Screening, Cancer Risk Factors
- High prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer
http://cancerpreventionresearch.aacrjournals.org/content/early/2018/09/29/1940-6207.CAPR-18-0014
- Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer
https://www.nature.com/articles/s41395-018-0395-y
- Coffee and pancreatic cancer risk among never‐smokers in the UK prospective Million Women Study
https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.31994
- Screening and surveillance in hereditary gastrointestinal cancers: Recommendations from the European Society of Digestive Oncology (ESDO) expert discussion at the 20th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona, June 2018
https://www.sciencedirect.com/science/article/pii/S0959804918313741
- Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches: Autoimmune diseases and pancreatic cancer risk
- A steady decline in pancreas transplantation rates
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30448085
BACKGROUND/OBJECTIVES: After years of growth in many pancreas transplant programs, UNOS has reported declining transplant numbers in the USA. This precipitating trend urges for an evaluation of the transplant numbers and scientific productivity in the Eurotransplant region and the UK. METHODS: We performed a trend analysis of pancreas transplantation rates, between 1997 and 2016, adjusting for changes in population size, and an analysis of scientific publications in this field. We used information from the UNOS, Eurotransplant, and UK transplant registry and bibliometric information from the Web of Science database. RESULTS: Between 2004 and 2016 there was an average annual decline in pancreas transplantation rates per million inhabitants of 3.3% in the USA and 2.5% in the Eurotransplant region. In the UK, transplant numbers showed an average annual decline of 1.0% from 2009 to 2016. Publications in Q1 journals showed an annual change of -2.1% and +20.1%, before 2004, and a change of -3.8% and -5.5%, between 2004 and 2016, for USA and Eurotransplant publications, respectively. CONCLUSIONS: Adjusting pancreas transplantation rates for changes in population size showed a clear decline in transplant numbers in both the USA and Eurotransplant region, with first signs of decline in the UK. Following this trend, the number of scientific publications in this field have declined worldwide.
- Prevalence of Asymptomatic Intraductal Papillary Mucinous Neoplasms in Healthy and Ill Populations Detected by Ultrasonography: A Single-Center Study of 6353 Outpatients
Pancreas 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30451793
OBJECTIVES: The aim of this study was to establish the prevalence of intraductal papillary mucinous neoplasms (IPMNs) without and with high-risk stigmata (HRS)/worrisome features (WF) and the epidemiologic association between IPMNs and other diseases. METHODS: Ultrasound examinations of outpatients were evaluated. The IPMN was confirmed by magnetic resonance imaging. The prevalence of IPMNs and HRS/WF IPMNs was calculated. The association between IPMNs and other diseases was studied. RESULTS: The prevalence rate of IPMNs was 3.4%. A total of 1,531,264 IPMNs were expected in Italian population (2.5%), whereas 2257 per 100,000 citizens (2.3%) were expected in the European standard population (ESP2013). The prevalence rates of HRS/WF IPMNs were 0.5%, 0.7%, and 0.6%, in our, the Italian, and the ESP2013 populations, respectively. A total of 432,881 and 620 HRS/WF IPMNs per 100,000 residents were expected in the Italian and the ESP2013 populations, respectively. The IPMN prevalence increased over 50 years of age (odds ratio [OR], 3.2; P < 0.001) and over 70 years of age (OR, 1.9; P < 0.001). Female sex was related to the presence of IPMNs (OR, 1.9; P < 0.001). CONCLUSIONS: Intraductal papillary mucinous neoplasms had a high prevalence in asymptomatic nonhospitalized populations. Age older than 50 years identified a possible risk category.
- Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion
http://ascopubs.org/doi/abs/10.1200/JCO.18.01489
- Contribution of biomarkers for pancreatic cancer-associated new-onset diabetes to pancreatic cancer screening
Pathology, research and practice 2018 Dec;214(12):1923-1928
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30477640
BACKGROUND: Pancreatic cancer (PaC) is one of the deadliest types of tumor, and it is regarded as a fatal disease, with a 5-year survival rate less than 10%. Most clinical diagnoses for PaC are made at an advanced stage because of the insidious onset of the disease, which leads to an extremely poor prognosis. RECENT FINDINGS: The relationship between diabetes mellitus (DM) and PaC has been established by several decades of research, and the prevalence of DM in patients with PaC has been reported to be 40%, with half of the patients having developed new-onset DM within 2 years or less. Increasing evidence suggests that new-onset DM is associated with a high prevalence of PaC, and PaC resection ameliorates DM. Therefore, screening for PaC may be needed in patients with newly developed DM. PURPOSE: The objective of this review was to present our current understanding of biomarkers for PaC-associated new-onset DM (PCAND), to offer a perspective on the prospects and problems of using this strategy for early screening to differentiate PCAND from new-onset type 2 DM not associated with PaC and to suggest candidate biomarkers to use for PaC screening in patients with new-onset DM. Finding sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.
- Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer
The American journal of gastroenterology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30353057
OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.
- Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries
Lancet (London, England) 2018 03;391(10125):1023-1075
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29395269
BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37·5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89·5% in Australia and 90·2% in the USA, but international differences remain very wide, with levels as low as 66·1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68·9%), colon (71·8%), and rectum (71·1%); in Japan for oesophageal cancer (36·0%); and in Taiwan for liver cancer (27·9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59·9% in South Korea, 52·1% in Taiwan, and 49·6% in China), and for both lymphoid malignancies (52·5%, 50·5%, and 38·3%) and myeloid malignancies (45·9%, 33·4%, and 24·8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49·8% in Ecuador to 95·2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28·9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation.
- Achieving better cancer intelligence for global cancer control
Lancet (London, England) 2018 03;391(10125):1003-1004
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29395271
- Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2018
Gastroenterology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315778
BACKGROUND & AIMS: Estimates of disease burden can inform national health priorities for research, clinical care, and policy. We aimed to estimate health care use and spending among gastrointestinal (GI) (including luminal, liver, and pancreatic) diseases in the United States. METHODS: We estimated health care use and spending based on the most currently available administrative claims from commercial and Medicare Supplemental plans, data from the GI Quality Improvement Consortium Registry, and national databases. RESULTS: In 2015, annual health care expenditures for gastrointestinal diseases totaled $135.9 billion. Hepatitis ($23.3 billion), esophageal disorders ($18.1 billion), biliary tract disease ($10.3 billion), abdominal pain ($10.2 billion), and inflammatory bowel disease ($7.2 billion) were the most expensive. Yearly, there were more than 54.4 million ambulatory visits with a primary diagnosis for a GI disease, 3.0 million hospital admissions, and 540,500 all-cause 30-day readmissions. There were 266,600 new cases of GI cancers diagnosed and 144,300 cancer deaths. Each year, there were 97,700 deaths from non-malignant GI diseases. An estimated 11.0 million colonoscopies, 6.1 million upper endoscopies, 313,000 flexible sigmoidoscopies, 178,400 upper endoscopic ultrasound examinations, and 169,500 endoscopic retrograde cholangiopancreatography procedures were performed annually. Among average-risk persons ages 50-75 years who underwent colonoscopy, 34.6% had 1 or more adenomatous polyps, 4.7% had 1 or more advanced adenomatous polyps, and 5.7% had 1 or more serrated polyps removed. CONCLUSIONS: GI diseases contribute substantially to health care use in the United States. Total expenditures for GI diseases are $135.9 billion dollars annually-greater than for other common diseases. Expenditures are likely to continue increasing.
- The Dutch Pancreas Biobank Within the Parelsnoer Institute: A Nationwide Biobank of Pancreatic and Periampullary Diseases
Pancreas 2018 04;47(4):495-501
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29521943
OBJECTIVES: Large biobanks with uniform collection of biomaterials and associated clinical data are essential for translational research. The Netherlands has traditionally been well organized in multicenter clinical research on pancreatic diseases, including the nationwide multidisciplinary Dutch Pancreatic Cancer Group and Dutch Pancreatitis Study Group. To enable high-quality translational research on pancreatic and periampullary diseases, these groups established the Dutch Pancreas Biobank. METHODS: The Dutch Pancreas Biobank is part of the Parelsnoer Institute and involves all 8 Dutch university medical centers and 5 nonacademic hospitals. Adult patients undergoing pancreatic surgery (all indications) are eligible for inclusion. Preoperative blood samples, tumor tissue from resected specimens, pancreatic cyst fluid, and follow-up blood samples are collected. Clinical parameters are collected in conjunction with the mandatory Dutch Pancreatic Cancer Audit. RESULTS: Between January 2015 and May 2017, 488 patients were included in the first 5 participating centers: 4 university medical centers and 1 nonacademic hospital. Over 2500 samples were collected: 1308 preoperative blood samples, 864 tissue samples, and 366 follow-up blood samples. CONCLUSIONS: Prospective collection of biomaterials and associated clinical data has started in the Dutch Pancreas Biobank. Subsequent translational research will aim to improve treatment decisions based on disease characteristics.
- Adolescent overweight and obesity and the risk for pancreatic cancer among men and women: a nationwide study of 1.79 million Israeli adolescents
Cancer 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30417331
BACKGROUND: There is growing concern regarding the impact of adolescent obesity on adult health. The objective of this study was to evaluate the association between body mass index (BMI) in late adolescence and the incidence of pancreatic cancer during adulthood. METHODS: The authors analyzed a cohort of 1087,358 Israeli Jewish men and 707,212 Jewish women who underwent a compulsory physical examination between ages 16 and 19 years from 1967 to 2002. Pancreatic cancer incidence through December 31, 2012 was identified by linkage to the national cancer registry. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer according to the US Centers for Disease Control and Prevention (CDC) BMI percentiles at baseline. RESULTS: Over a median 23 year follow-up, 551 incident cases of pancreatic cancer cases occurred (423 men; 128 women). Compared with normal weight (5th to-<85th percentile), obesity (≥95th percentile) was associated with an increased risk of cancer among both men (HR, 3.67; 95% confidence interval [CI], 2.52-5.34) and women (HR, 4.07; 95% CI, 1.78-9.29). Among men, compared with low-normal BMI (≥5th to <25th percentile), high-normal BMI (≥75th to <85th percentile) and overweight (85th to 95th percentile) also were associated with a higher risk for cancer(high-normal BMI: HR, 1.49; 95% CI, 1.05-2.13; overweight: HR, 1.97; 95% CI, 1.39-2.80). The estimated population-attributable fraction because of overweight and obesity was 10.9% (95% CI, 6.1%-15.6%). CONCLUSIONS: Men and women who were obese or overweight as adolescents are at an increased risk for subsequent pancreatic cancer.
- A prospective clinical and biological database for pancreatic adenocarcinoma: the BACAP cohort
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4906-4
Bile Ducts
- Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma
Virchows Archiv : an international journal of pathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30377796
Intrahepatic cholangiocarcinoma (ICC) has universally poor outcome, mainly due to its late clinical presentation. Identification of specific biomarkers and development of effective treatment are still urgently required. Mutations in PBRM-1 and BAP-1 genes, and the expression of S100P have been related to survival in ICC. miR-31 seems also to play important regulatory functions in ICC and it directly regulates BAP-1 expression in lung cancer. In this study, tissue expression of BAP-1, PBRM-1, S100P, and miR-31 was investigated in ICC and correlated with clinical-pathological features. Sixty-one consecutive patients who underwent curative hepatic resection for ICC were enrolled. None received any therapy prior to surgery. Immunostaining for BAP-1, PBRM-1, and S100P, and in situ hybridization for miR-31 were performed, using tissue microarray slides. A strong retained expression of BAP-1 and PBRM-1 was associated with a reduced overall (p = 0.04 and p = 0.002, respectively) and disease-free survival (p = 0.05 and p = 0.02, respectively). An overexpression of S100P was related to a reduced overall survival (p = 0.005). The multivariate analyses identified the presence of perineural invasion and the retained PBRM-1 expression as independent predictors of worse overall [p = 0.02, hazard ratio (HR) = 2.25 (1.16-4.39) and p = 0.001, HR = 3.13 (1.56-6.28), respectively] and disease-free survivals [p = 0.03, HR = 2.43 (1.09-5.4) and p = 0.03, HR = 2.51 (1.11-5.67), respectively]. An overexpression of S100P was predictive of a worse overall survival [p = 0.02, HR = 1.66 (1.08-2.55)]. High levels of miR-31 were significantly associated to a low expression of BAP-1 protein (p = 0.03). In ICC, a retained expression of BAP-1 and PBRM-1, and an overexpression of S100P are related to a poor prognosis.
- Pancreatic-Type Mixed Acinar Neuroendocrine Carcinoma Arising in the Common Bile Duct: A Case Report
- Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma
https://www.nature.com/articles/s41416-018-0199-2
- Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma
- Double Trouble: A Rare Case of Concurrent Biliary Adenofibroma and Hepatobiliary Mucinous Cystic Neoplasm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195646/
- Outcomes of surgery for 2010 WHO classification-based intraductal papillary neoplasm of the bile duct: Case–control study of a single Japanese institution’s experience with special attention to mucin expression patterns
https://www.ejso.com/article/S0748-7983(18)31936-X/fulltext
- Comparison of the Clinicopathologic Characteristics of Intraductal Papillary Neoplasm of the Bile Duct according to Morphological and Anatomical Classifications
https://www.jkms.org/search.php?where=aview&id=10.3346/jkms.2018.33.e266&code=0063JKMS&vmode=FULL
- When the immune system is away biliary cancer cells may come back to play
- Patterns of gene mutations in bile duct cancers: is it time to overcome the anatomical classification?
https://www.hpbonline.org/article/S1365-182X(18)30877-3/abstract
- Surgical resection of lymph node positive intrahepatic cholangiocarcinoma may not improve survival
https://www.sciencedirect.com/science/article/pii/S1365182X18339352
- Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis
Pathology oncology research : POR 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30448973
Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal-infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials.
- Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis
https://link.springer.com/article/10.1007/s12253-018-0491-8
- Impact of microvascular invasion on clinical outcomes after curative‐intent resection for intrahepatic cholangiocarcinoma
https://onlinelibrary.wiley.com/doi/10.1002/jso.25305
- Frequency of bile duct confluence variations in subjects with pancreas divisum: an analysis of MRCP findings
Diagnostic and interventional radiology (Ankara, Turkey) 2018 5;24(2):72-76
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29757145
PURPOSE: We aimed to evaluate the frequency of bile duct branching pattern variations at the hepatic confluence in patients with pancreas divisum (PD). METHODS: A search was performed through the hospital database using the keyword “pancreas divisum” to identify patients. The magnetic resonance cholangiopancreatography (MRCP) images of 137 patients who were diagnosed with PD between August 2011 and November 2016 were retrospectively analyzed for the presence of bile duct variations. A control group of 137 patients without PD was established among patients investigated during the same period. Variations of the biliary tract were grouped into seven types according to the McSweeney et al. classification. RESULTS: Biliary tract variations were detected in 103 of a total of 274 patients. Fifty-eight PD patients (42.3%) and 45 control patients (32.8%) had bile duct variation at the hepatic confluence level. The patients with PD were more likely to have biliary tract variation compared with the control group; however, it was not statistically significant (P = 0.105). The most common variation in PD patients was type 3a variation (16.8%). CONCLUSION: MRCP studies showed atypical bile duct confluence pattern in nearly half of both PD patients and controls. There was no statistically significant difference in the frequency of anatomic variations at bile duct confluence in patients with PD versus those without PD. Derivation of these structures from different outpouchings in early embryological life may explain this insignificant difference.
- ASO Author Reflections: Re-resection of Positive Bile Duct Margin for Hilar Cholangiocarcinoma
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30288652
- Cholangiocarcinoma
Surgical pathology clinics 2018 Jun;11(2):403-429
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29751883
This article focuses on cholangiocarcinoma, both intrahepatic and extrahepatic. The various classification schemes based on anatomic location, macroscopic growth pattern, microscopic features, and cell of origin are outlined. The clinicopathologic, immunohistochemical and molecular differences between intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, as well as differences in the 2 subtypes of intrahepatic cholangiocarcinoma, are discussed. Finally, precursor lesions, prognosis, treatment, and promising new potential targeted therapies are reviewed.
- EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma
Virchows Archiv : an international journal of pathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30349952
Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.
Staging
Bile Duct TNM staging, Margins, Survival
- Prognostic comparison of the 7th and 8th editions of the American Joint Committee on Cancer staging system for intrahepatic cholangiocarcinoma
Journal of hepato-biliary-pancreatic sciences 2018 Apr;25(4):240-248
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29450978
BACKGROUND: Several important changes were made to the 8th edition of the American Joint Committee on Cancer (AJCC) tumor staging system for intrahepatic cholangiocarcinoma (ICC). We assessed the prognostic impact of this new tumor staging system compared to the 7th edition. METHODS: A retrospective single-institution study was performed with 626 patients who underwent R0 resection for ICC over 20-year period. RESULTS: Anatomical resection and concurrent bile duct resection were performed in 571 (91.2%) and 62 (9.9%) patients, respectively. Cumulative tumor recurrence and patient survival rates were 40.6% and 73.3% at 1 year; 66.7% and 43.8% at 3 years; 73.6% and 30.4% at 5 years; and 74.4% and 20.3% at 10 years, respectively. Independent prognostic factors for tumor recurrence and patient survival were multiple tumors, carbohydrate antigen 19-9 >200 U/ml, tumor size >5 cm, direct invasion to extrahepatic structure, and lymph node metastasis. For tumor-node-metastasis stages in the 7th versus the 8th editions, concordance index was 0.615 and 0.625 for tumor recurrence and 0.626 and 0.628 for patient survival, respectively. CONCLUSIONS: The 8th edition of the AJCC staging system appears to provide high prognostic contrast for T stage categories, except for T3. However, overall prognostic performance of the 8th edition was not markedly improved over the 7th edition.
Epidemiology, Screening, Cancer Risk Factors
- Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink
Gut 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30448774
OBJECTIVE: To evaluate the association between statin use and risk of biliary tract cancers (BTC). DESIGN: This is a nested case-control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders. RESULTS: We included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007). CONCLUSION: Compared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.
- Pattern of distant metastases in primary extrahepatic bile-duct cancer: A SEER-based study
Cancer medicine 2018 Oct;7(10):5006-5014
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30277653
Extrahepatic bile duct cancer (EBDC) is a combined type of malignancy mainly consisting of extrahepatic cholangiocarcinoma and gallbladder cancer. Clinically, it is featured with latent symptoms and early metastasis, leading to a poor prognosis. Therefore, this cohort study aimed to depict the possible metastatic patterns of EBDC of diverse sub-types and evaluate the prognostic significance of diverse metastatic destinations with data from the clinical database. Relevant data of total 4061 confirmed EBDC patients diagnosed between 2010 and 2013 from the Surveillance, Epidemiology and End Results (SEER) database was obtained. We applied t test to describe the baseline data of patients included and used chi-square test to compare the distribution of distant metastatic sites. We further adopted odds ratio assess the combined metastatic patterns and compared survival difference of patients with different distal metastasis organ by Kaplan-Meier analysis. We identified totally 4061 patients over 18 years old diagnosed with extrahepatic bile tract malignancies between 2010 and 2013, with clear metastatic status and follow-up data, without primary malignancies. Liver and distant lymph (DL) are the two most common sites as a single metastasis organ. In combined metastasis patterns, bi-organ is more frequent than the other types. Lung is the organ preferentially for bi-organ metastasis, while bone and distant lymph similarly intend to co-metastasize with brain. Distal metastasis in EBDC patients indicates an extremely poor prognosis. According to the final analysis results, malignancies in extrahepatic bile duct exhibit similar metastatic patterns, suggesting that we can regard them as a unity to assess its development. Profound differences exist in distribution of distant extrahepatic metastatic sites and their combinations. Results from our studies would provide some information for follow-up strategies and future studies.
Gallbladder
Morphology, Diagnostics, IHC
Morphology, Diagnostics, IHC
- MUC5B, CA9 and CLDN18 are potential theranostic markers of gallbladder carcinoma
https://onlinelibrary.wiley.com/doi/10.1111/his.13797
- Intracystic Papillary Neoplasm of the Gallbladder Arising from a Localized Adenomyomatous Hyperplasia
https://www.kjpbt.org/upload/pdf/kpba-23-4-182.pdf
- Differential diagnosis of gallbladder ascariasis debris: the added value of contrast enhanced ultrasound with high frequency transducer
- Diffuse Intracystic Papillary Neoplasm Indistinguishable from Gallbladder Cancer: A Case Report
https://www.jstage.jst.go.jp/article/twmuj/advpub/0/advpub_2018006/_pdf
- Five year experience of gallbladder polyp surveillance and cost effective analysis against new European consensus guidelines
https://www.sciencedirect.com/science/article/abs/pii/S1365182X18344873
- Intracholecystic papillary-tubular neoplasm in a patient with choledochal cyst and anomalous pancreaticobiliary junction: case report
https://www.birpublications.org/doi/pdfplus/10.1259/bjrcr.20180079
- Intracholecystic papillary–tubular neoplasm of gallbladder: A 5-year retrospective pathological study
- A case report of intracholecystic papillary neoplasm of the gallbladder resembling a submucosal tumor
https://link.springer.com/article/10.1186/s40792-018-0524-2
- Outcomes of surgical resection of gallbladder cancer in patients presenting with jaundice: A systematic review and meta‐analysis
https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25186
- Unexpectedly High Prevalence of Cystoisospora belli Infection in Acalculous Gallbladders of Immunocompetent Patients
American journal of clinical pathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30285068
Objectives: Indications for cholecystectomy have changed dramatically over the past three decades. Cystoisospora belli has been reported in cholecystectomy specimens of immunocompetent patients. The present study was designed to determine the prevalence and clinical association of C belli in the gallbladder. Methods: The study included retrospective review of cholecystectomy specimens (n = 401) removed for various indications, and a prospective cohort of cholecystectomy specimens (n = 22) entirely submitted for histologic evaluation. Correlations of presence of C belli with age, sex, clinical indication, and abnormalities of preoperative laboratory values were assessed by Fisher exact test. Results: C belli was identified in 39/401 (9.7%) of the retrospective cohort, and 6/22 (27.3%) of the entirely submitted specimens. The presence of C belli showed no correlation with age, sex, clinical indication, or laboratory abnormalities. Conclusions: C belli resides in a latent state in the gallbladder and may be best considered a commensal organism.
- Intravascular Large B-Cell Lymphoma of the Gallbladder
Turkish journal of haematology : official journal of Turkish Society of Haematology 2018 May;35(2):145-146
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29391332
Staging
Gallbladder TNM staging, Margins, Survival
- Gallbladder polypoid lesions >15mm as indicators of T1b gallbladder cancer risk
Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology 2017 Sep;18(3):156-158
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28958638
BACKGROUND AND STUDY AIMS: Gallbladder polyps (GBPs) are found in 5-7% of the adult population. However, it is very important to differentiate between benign and malignant polyps to establish an appropriate treatment. The present study aimed to determine the relevance of the 10-mm size criterion and attempted to determine the cut-off diameter of T1b tumours, which requires additional surgical intervention. PATIENTS AND METHODS: Cases with GBPs were collected between January 2005 and January 2015. A total of 109 patients were enroled retrospectively. Information on age, sex, ultrasound findings, and blood laboratory tests was reviewed. The 10-mm criterion and T1b tumours were examined. RESULTS: Sixty-nine females and 40 males were included in the study. Patient age was 45±10.7years (range 27-70years). The 10-mm cut-off sensitivity and specificity for predicting malignant polyps was 93.6% and 85.2%, respectively. Fifteen patients had malignant pathologic results, and one patient had GBP <10mm (intraepithelial, 8mm). Two patients had intraepithelial tumours of 12 and 13mm. Twelve malignant patients had T1b tumours with polyp sizes >15mm. CONCLUSION: Gallbladder cancer may occur in polyps of <10mm. Larger size and older age were predictors of neoplastic GBPs. We suggest 15mm as the optimal cut-off point to predict T1b cancer.
- ASO Author Reflections: Gallbladder Cancer Predictive Risk Score Based on Pathological Findings: A Propensity Score-Matched Analysis
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315386
- Optimal Surgical Treatment in Patients with T1b Gallbladder Cancer: An International Multicenter Study
https://onlinelibrary.wiley.com/doi/abs/10.1002/jhbp.593
- Impact of the number of examined lymph nodes on outcomes in patients with lymph node-negative gallbladder carcinoma
World journal of gastroenterology 2018 Jul;24(26):2886-2892
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30018483
AIM: To determine whether the number of examined lymph nodes (LNs) is correlated with the overall survival of gallbladder carcinoma (GBC) patients. METHODS: Patients were collected from the Surveillance Epidemiology and End Results database (2004-2013) and categorized by the number of LNs into six groups: 1 LN, 2 LNs, 3 LNs, 4 LNs, 5 LNs, and ≥ 6 LNs. Survival curves for overall survival were plotted with a Kaplan-Meier analysis. The log-rank test was used for univariate comparisons. RESULTS: In a cohort of 893 patients, the median number of examined LNs was two for the entire cohort. The survival for the 1 LN group was significantly poorer than those of the stage I and II disease groups and for the entire cohort. By dichotomizing the number of LNs from 1 to 6, we found that the minimum number of LNs that should be examined was four for stage I, four or five for stage II, and six for stage IIIA disease. Therefore, for the entire cohort, the number of examined LNs should be at least six, which is exactly consistent with the American Joint Committee on Cancer criteria. CONCLUSION: The examination of higher numbers of LNs is associated with improved survival after resection surgery for N0 GBC. The guidelines for GBC surgery, which recommend that six LNs be examined at least, are statistically valid and should be applied in clinical practice widely.
Ampulla of Vater
Morphology, Diagnostics, IHC
Morphology, Diagnostics, IHC
- Metastatic melanoma in the ampulla of Vater
Gastrointestinal endoscopy 2018 Apr;87(4):1156-1158
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28989008
- Long-term complete remission of a patient with high grade neuroendocrine carcinoma of ampulla of Vater
BMJ case reports 2018 Jun;2018():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29950363
We describe a case report of a 53-year-old man with a 5-months history of progressive jaundice and upper abdominal pain. The patient was further evaluated and finally diagnosed with a high-grade ampullary neuroendocrine tumour (based on endoscopic-guided biopsy). Thereafter, he underwent pancreatoduodenectomy and adjuvant platinum-based chemotherapy. This extremely rare case presents his long-lasting disease-free survival compared with similar cases; this case report exemplifies a new, potentially efficient method for treating high-grade papillary neuroendocrine tumour and may pave the way for further clinical trials utilising this blueprint in the treatment of related conditions.
- Continuing Advancements in Diagnosis and Management of Ampullary Adenoma
The American surgeon 2017 Aug;83(8):e302-304
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28822368
- Duodenal Epithelial Polyps
http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2018-0034-RA
- How to Approach a Patient With Ampullary Lesion
Gastroenterology 2018 12;155(6):1670-1676
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30419205
- Microanatomical profiles on the lymphatic system in the human ampulla of Vater (immunohistochemistry and scanning electron microscopy)
Journal of hepato-biliary-pancreatic sciences 2017 Oct;24(10):570-575
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28846834
BACKGROUND: Little information is available regarding microanatomy of lymphatic system in the ampulla of Vater, though it is of critical importance for an understanding of tumor progression via the lymphatics and determination of surgical strategy. The present study, therefore, aimed to demonstrate the distribution and microanatomical profiles on the lymphatic system in the ampulla. METHODS: The fine distribution and structure of the lymphatic vessels were investigated in the ampulla and the stomach by immunohistochemistry for lymphatic- (D2-40) and blood vascular- (CD31) specific markers and scanning electron microscopy. The densities of lymphatic and blood vessels were also compared. RESULTS: The duodenal papilla densely developed the lymphatics with distinct aspects of lymphatic capillaries, together with blood vessels. The density of lymphatic capillaries in the extramuscular layer in the ampulla was higher than those of both the other ampullary layers and the gastric extramuscular (subserosal) layer. CONCLUSIONS: The ampulla of Vater showed widespread lymphatic capillaries throughout the entire wall. The specific vascular system is suited to produce lymph everywhere and drain without via such a large vessel as lymphatic collector. This suggests that tumor cells invade the lymphatics and metastasize more easily in the ampulla than in the other gastrointestinal regions.
- A Rare Case of Ampullary Goblet Cell Carcinoid
Internal medicine (Tokyo, Japan) 2018 Sep;57(17):2489-2496
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29607953
An asymptomatic 70-year-old woman was referred to our hospital because of liver enzyme elevation. Enhanced abdominal computed tomography demonstrated a small, round-shaped tumor with dilation of the common bile duct and main pancreatic duct. A biopsy specimen from the papilla showed mucin-containing cells that were positive for endocrine markers on immunohistochemical staining. Endoscopic snare resection was done, and there was a positive vertical margin on pathology. Pancreaticoduodenectomy was then performed later. The final diagnosis was goblet cell carcinoid, pT2N0M0, pStage IIA [Union for International Cancer Control (UICC) 7th edition]. Ampullary goblet cell carcinoid is an extremely rare disease of which there have been no recent reports.
- Duodenal tumor risk in Lynch syndrome
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30448460
BACKGROUND AND AIMS: Lynch syndrome (LS) is associated with an increased risk of small bowel tumors but routine screening is not recommended in international guidelines. The aim of our study was to determinate the prevalence of duodenal tumors in a French cohort of LS patients. METHODS: Patients carrying a germline pathogenic variant in a MMR gene, supported by our local network, in which at least one upper endoscopy had been performed, were included. We registered the occurrence of duodenal lesions in those patients. RESULTS: 154 LS patients were identified including respectively 85 MSH2 and 41 MLH1 mutated patients respectively. Seven out of 154 (4.5%) had at least one duodenal lesion. Median age at diagnosis was 58 years (range: 49-73). The twelve lesions locations were: descending duodenum (n = 7), genu inferius (n = 2), duodenal bulb (n = 1), ampulla (n = 1), fourth duodenum (n = 1). Three lesions were invasive adenocarcinomas. The incidence rate of duodenal lesions in patients with MSH2 or MLH1 pathogenic variants was respectively 7.1% (6 out of 85) and 2.4% (1 out of 41) emphasizing a trend toward increased risk of developing duodenal lesion in MSH2 mutated patients: OR: 5.17, IC95% (0.8-60.07), p = 0.1307. CONCLUSION: Regarding this high prevalence rate, especially in MSH2 patients, regular duodenal screening during upper endoscopy should be considered in routine in LS patients.
- Ampulla of Vater carcinoma: Molecular landscape and clinical implications
https://www.wjgnet.com/1948-5204/full/v10/i11/370.htm
- Gangliocytic Paraganglioma with Carcinoma of the Ampulla of Vater
Internal medicine (Tokyo, Japan) 2018 Sep;57(18):2663-2668
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29780117
The patient was a “73” -year-old woman who visited our hospital with the chief complaint of weight loss. Upper gastrointestinal endoscopy revealed an enlarged ampulla of Vater, and a biopsy led to a diagnosis of Group “4” gastric carcinoma; suspicious of adenocarcinoma. There were no findings suggesting invasion into the muscle layer of duodenum, despite tumor mass formation being observed in the sphincter of Oddi. We performed endoscopic papillectomy for both diagnostic and therapeutic purposes. Pathologically, a well-differentiated adenocarcinoma existed in the superficial layer of the mucous membrane of the papilla of Vater, and gangliocytic paraganglioma was present in the deep portion. The resected margins of both lesions were negative.
- Adenosquamous carcinoma of the papilla of Vater: A phenotypic heterogeneity characterized by a common molecular landscape
https://onlinelibrary.wiley.com/doi/10.1111/pin.12731
- ASO Author Reflections: Current Treatment Options for Duodenal Adenocarcinoma-A Call for Collaborative Studies
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30327972
Staging
Ampulla of Vater TNM staging, Margins, Survival
- Perineural Invasion is a Strong Prognostic Moderator in Ampulla of Vater Carcinoma: A Meta-analysis
Pancreas 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30451797
OBJECTIVE: Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC. METHODS: Using PubMed and SCOPUS databases, we conducted the first systematic review and meta-analysis on this topic. RESULTS: Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality of more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality of more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence of more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]). CONCLUSIONS: Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior.
- Validation of the eighth edition of the American Joint Committee on Cancer staging system for ampulla of Vater cancer
Surgery 2018 05;163(5):1071-1079
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29452703
BACKGROUND: The American Joint Committee on Cancer recently proposed the eighth edition of cancer staging system. Validation studies are required to evaluate the prognostic stratification of ampulla of Vater cancer patients. METHODS: In the study, 369 operatively resected patients with ampullary cancers were grouped based on the eighth T (T1a, limited to sphincter of Oddi; T1b, invasion to duodenal submucosa; T2, invasion to duodenal proper muscle; T3a, invasion to pancreas ≤0.5 cm; T3b, invasion to pancreas >0.5 cm; and T4, involvement of celiac axis or superior mesenteric artery) and N (N0, no nodal metastasis; N1, 1-3 nodal metastasis; and N2, ≥4 nodal metastasis) category of ampullary cancer staging. RESULTS: Overall 5-year survival rates for T and N categories were as followed: T1a, 83%; T1b, 71%; T2, 46%; T3a, 48%; T3b, 28.5%, T4, 7% (P< .001); N0, 44.8%; N1, 20%; N2, 4% (P < .001). Pair-wise comparisons demonstrated significant differences between T1a-b (P = .005), T3a-T3b (P = .03), N0-N1 (P < .001), and N1-N2 (P = .007) tumors, but not between T1b-T2 (P = .20), T2-T3a (P = .84), and T3b-T4 (P = .17) lesions. CONCLUSION: The eighth edition T category for ampullary cancer does not stratify patients accurately with regard to prognosis. Modification of the current T category with eliminating subcategories (T1, invasion to duodenal submucosa; T2, invasion to duodenal proper muscle; T3, invasion to pancreas or duodenal subserosa) is a better way for determining prognosis of ampullary cancer. The current N category segregates patient survival well.
- Prognostic role of metastatic lymph node number and lymph node ratio in ampullary adenocarcinoma
http://cancer-research-frontiers.org/wp-content/uploads/2018/10/CRF-1833-4-1.pdf
- Perineural Invasion is a Strong Prognostic Moderator in Ampulla of Vater Carcinoma A Meta-analysis
- Adjuvant radiotherapy following pancreaticoduodenectomy for ampullary adenocarcinoma improves survival in node-positive patients: a propensity score analysis
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2018 Sep;20(9):1212-1218
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29497964
INTRODUCTION: This study aimed to evaluate the impact of adjuvant radiotherapy in patients undergoing pancreaticoduodenectomy (PD) for ampullary adenocarcinoma. METHODS: Using the Surveillance, Epidemiology, and End Results, patients with non-metastatic ampullary adenocarcinoma between 2004 and 2013 were identified. Cancer-specific survival and overall survival were estimated using Kaplan-Meier and Cox regression to obtain adjusted hazard ratio of survival. RESULTS: In this study, 1106 patients with ampullary adenocarcinoma were identified, of which 27% received adjuvant radiotherapy and the remaining 73% (803/1106) patients did not receive any adjuvant radiotherapy. In the matched cohort, there were still no significant difference in CSS (median 41 vs 35, p = 0.28) and OS (median 32 vs 30, p = 0.26) between patients receiving adjuvant radiotherapy and those under observation alone. However, in patients with N2 (Fig. 4) disease, both CSS (median 27 vs 19 months, p = 0.0044) and OS (median 23 vs 17 months, p = 0.0091) were significantly longer for patients receiving adjuvant radiotherapy. CONCLUSION: In summary, adjuvant radiotherapy following PD for ampullary adenocarcinoma significantly improves survival in patients with N2 disease. Future studies defining “high-risk” groups using larger cohorts will enable reliable appraisal on the benefit of adjuvant radiotherapy to allow for a more personalized approach in treating patients.
- Pancreaticoduodenectomy for periampullary tumours: a review article based on Surveillance, End Results and Epidemiology (SEER) database
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2018 Sep;20(9):1153-1160
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29335829
INTRODUCTION: This study set to examine relative survival of patients with periampullary cancers undergoing pancreaticoduodenectomy (PD). METHODS: Using the Surveillance, End Results and Epidemiology (SEER) database, this study identified 9877 patients with non-metastatic pancreatic adenocarcinoma who underwent PD between 2004 and 2013. RESULTS: Ampullary carcinomas have the best survival among periampullary malignancies. Lymph node ratio is a significant prognostic factor, even when stratified by tumour types. Patients receiving adjuvant radiotherapy following PD have superior survival than patients without radiotherapy (median 25 vs 20 months, p < 0.001), particularly ductal adenocarcinoma (HR: 0.74, CI95% 0.69-0.78; p < 0.001), cholangiocarcinoma (HR: 0.75, CI95% 0.59-0.97; p = 0.027), and ampullary carcinoma (HR: 0.79, CI95% 0.64-0.98; p = 0.029) with greatest survival benefit at 1-year postresection. CONCLUSION: Future studies aiming to further define genetic signatures of individual periampullary cancers would allow a personalised therapeutic approach in improving survival.
- [Prognostic factors in adenocarcinoma of the ampulla of Vater]
Revista espanola de patologia : publicacion oficial de la Sociedad Espanola de Anatomia Patologica y de la Sociedad Espanola de Citologia 2018 04;51(4):210-215
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30269771
INTRODUCTION: Ampullary adenocarcinoma seems less aggressive than other pancreato-biliary neoplasms. The aim of this study is to define determining prognostic factors. MATERIAL AND METHODS: Retrospective case series from a large tertiary Hospital including all patients diagnosed with ampullary adenocarcinoma who underwent cephalic pancreatoduodenectomy with curative intent. Outcome variables have been progression free survival and overall survival. RESULTS: 24 patients were included. 54.2% were females and the mean age was 72.5 (45-85). Most cases were of intestinal type (50%), followed by pancreatobiliary (37.5%) and mucinous. Only 8.3% were high histopathological grade. Vessel invasion was detected in 31.8% of the cases and perineural infiltration in 20.8%. A large percentage of cases showed no lymph node involvement at the time of diagnosis (54.1%). Most cases were stage T1 or T3 (39.1 y 43.5%, respectively). 34.8% of the patients recurred, mainly in regional lymph nodes (62.5% of the recurrences) and they all died of tumor, mainly during the first year after diagnosis. Multivariate analysis with Cox regression model revealed that only lymph node involvement was independently associated to a shorter disease free progression interval and overall survival. CONCLUSIONS: Lymph node involvement was the most important predictive factor for ampullary adenocarcinoma in this series.
Neuroendocrine
PanNet
PanNET, Pancreatic Neuroendocrine Tumors and related neuroendocrine neoplasms
- Comparison of Monitor-Image and Printout-Image Methods in Ki-67 Scoring of Gastroenteropancreatic Neuroendocrine Tumors
Endocrine pathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30367334
Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are classified according to tumor grade. Ki-67 and mitotic count are the two determinants of this classification. Therefore, Ki-67 scoring becomes very important in classifying the patients accurately. Eye-balling, counting of cells through the microscope, automated image analysis systems, and manual counting of printed image are the four major scoring methods in use. The aim of this study is to show the agreement between monitor-image method (MIM) and printout-image method (PIM) of Ki-67 scoring. In our study, 120 GEP-NETs from 85 patients diagnosed between January 2005 and July 2017 were evaluated. Thirty-seven cases with either polypectomy or resection material were selected. Seven different scoring methods using either a monitor-image or a printout-image were applied for Ki-67 scoring. They are as follows: whole-PIM, 1/9-PIM, whole-MIM, 1/4-MIM, 1/6-MIM, 1/9-MIM, and 1/12-MIM. In the comparison of Ki-67 scoring methods, intraclass correlation coefficients ranging from 0.951 to 0.999 were found. The Bland-Altman analysis showed near-perfect agreement between whole-MIM and whole-PIM as well as 1/9-MIM and 1/9-PIM. The level of agreements among the other methods were sufficient too, but there was a relative decrease in the level of agreement as the area of counting becomes smaller. The average application time decreased from 373.7 to 41.7 s gradually as the scoring area becomes smaller. Our study shows that there is a remarkable agreement between the MIM and PIM used in Ki-67 scoring.
- Pancreatic VIPomas from China: Case reports and literature review
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30391116
Vasoactive intestinal polypeptide-secreting tumors (VIPomas) are rare neuroendocrine tumors that often present as watery diarrhea, hypokalemia, and achlorhydria or hypochlorhydria. In this study, we present our institutional experience of diagnosis and treatment of VIPomas, along with a review of the Chinese literature since 1980. Patient #1, diagnosed in 1984 and with intact clinical records, shows the natural history of this disease. Patient #2, diagnosed in 2015, shows the results of evaluation by nuclear medicine techniques and the outcomes of standardized treatment. Comprehensive review of 41 cases allows evaluation of clinical characteristics, treatments and outcomes of pancreatic VIPoma patients. All patients presented with watery diarrhea. The average stool volume reached 3247 mL per day. Average serum VIP level was 839.3 ng/L. Twelve of the 41 cases were reported to have metastases at diagnosis. Somatostatin receptor scintigraphy and 18FDG PET-CT are efficient methods for detection of VIPoma. Surgical excision can promptly alleviate hormonal symptoms.
- Natural History of Small Pancreatic Lesions Suspected to Be Nonfunctioning Pancreatic Neuroendocrine Tumors
Pancreas 2018 10;47(10):1357-1363
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30308537
OBJECTIVES: Nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are a rare disease but have been diagnosed more frequently than before. The aim of this study was to evaluate the natural course of small NF-PNETs. METHODS: We performed a retrospective analysis of patients with incidentally found small NF-PNETs (<20 mm) from 1999 to 2015. The patients who were recommended surveillance were included. RESULTS: There were 69 patients with small NF-PNETs with a mean size of 10.9 (standard deviation [SD], 3.1) mm. The average follow-up period was 52.2 (SD, 38.7) months. The changes in tumor size were as follows: increased (13.0%), sustained (84.1%), and decreased (2.9%). Eighteen were evaluated with grade 1 NF-PNETs and 1 with grade 2 among the obtained tissues. Thirteen patients underwent surgery after an average 32.9 (SD, 42.6) months later. There were 7 patients of Ia, 1 of Ib, 2 of IIa, and 1 of IIb according to the pathologic stages. Two patients received reoperation for recurrent tumors, and 2 patients showed distant metastasis after surgery, but no disease-related death occurred. CONCLUSIONS: Most of the small NF-PNETs did not increase in size and seldom showed metastasis. The wait-and-see strategy can be used for NF-PNETs less than 2 cm.
- Incidentally detected pancreatic neuroendocrine microadenoma with lymph node metastasis
https://link.springer.com/article/10.1007/s00428-018-2407-0
- Comparison of Monitor-Image and Printout-Image Methods in Ki-67 Scoring of Gastroenteropancreatic Neuroendocrine Tumors
https://link.springer.com/article/10.1007/s12022-018-9554-3
- Immunohistochemical Biomarkers of Gastrointestinal, Pancreatic, Pulmonary, and Thymic Neuroendocrine Neoplasms
Endocrine pathology 2018 Jun;29(2):150-168
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29520563
Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations that irrespective of their primary site share features of neural and endocrine differentiation including the presence of secretory granules, synaptic-like vesicles, and the ability to produce amine and/or peptide hormones. NENs encompass a wide spectrum of neoplasms ranging from well-differentiated indolent tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. Most cases arise in the digestive system and in thoracic organs, i.e., the lung and thymus. A correct diagnostic approach is crucial for the management of patients with both digestive and thoracic NENs, because their high clinical and biological heterogeneity is related to their prognosis and response to therapy. In this context, immunohistochemistry represents an indispensable diagnostic tool that pathologists need to use for the correct diagnosis and classification of such neoplasms. In addition, immunohistochemistry is also useful in identifying prognostic and theranostic markers. In the present article, the authors will review the role of immunohistochemistry in the routine workup of digestive and thoracic NENs.
- Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms
https://cyberleninka.org/article/n/1491696
- Well differentiated neuroendocrine tumors, a single center experience
https://www.sciencedirect.com/science/article/pii/S2452336418300566
- DAXX Mutation Status of Embolization-Treated Neuroendocrine Tumors Predicts Shorter Time to Hepatic Progression
https://www.sciencedirect.com/science/article/pii/S1051044318312491
- The use of Ki-67 labeling index to grade pulmonary well-differentiated neuroendocrine neoplasms: current best evidence
https://www.nature.com/articles/s41379-018-0076-9
- COMPETITIVE TESTING THE WHO 2010 VS THE WHO 2017 GRADING OF PANCREAS NEUROENDOCRINE NEOPLASIA: DATA FROM A LARGE INTERNATIONAL COHORT STUDY
https://www.karger.com/Article/Abstract/494355
- Ki-67 and presence of liver metastases identify different progression-risk classes in pancreatic neuroendocrine neoplasms (pNEN) undergoing resection
https://www.ejso.com/article/S0748-7983(18)31452-5/fulltext
- Gastroenteropancreatic Neuroendocrine Tumors
https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21493
- Imaging presentation of pancreatic neuroendocrine neoplasms
https://link.springer.com/article/10.1007/s13244-018-0658-6
- Case Report: Can a high-grade neuroendocrine carcinoma be functional?
https://www.sciencedirect.com/science/article/abs/pii/S0002962918304142
- Association between preoperative Vasostatin-1 and pathological features of aggressiveness in localized nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET)
https://www.sciencedirect.com/science/article/pii/S142439031830752X
- Limited role of Chromogranin A as clinical biomarker for pancreatic neuroendocrine tumors
https://www.sciencedirect.com/science/article/abs/pii/S1365182X18344666
- High Minichromosome maintenance protein 7 proliferation indices: a powerful predictor of progression in pancreatic neuroendocrine neoplasms without distant metastasis at the time of surgery
Human pathology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30447299
Pancreatic neuroendocrine neoplasms (PanNENs) have an unpredictable clinical course that varies from indolent to highly malignant. No immunohistochemical markers are available for reliable prediction of the biological behavior of early-stage PanNENs. Minichromosome maintenance protein 7 (MCM7) is a putative powerful marker of cell proliferation. Whether the expression of MCM7 is related to the risk of PanNENs progression remains unclear. We assessed the clinical behavior of 156 PanNENs with respect to stage, grade, Ki-67 index, MCM7 index, and other pathologic features. A high MCM7 index was significantly associated with larger tumor size (P<.001), nonfunctioning tumor (P<.001), increased grade (P<.0001), and later TNM stage (P<.001). In multivariate analysis, G2/G3 (hazard ratio (HR), 2.21; 95% confidence interval (CI), 1.35-3.62; P<.001), stage III/IV (HR, 2.11; 95% CI, 1.31-3.41; P<.001), and MCM7 labeling index (LI)>5% (HR, 3.81; 95% CI, 1.30-11.17; P=.02) were independent negative prognostic factors related to the risk of tumor progression in stage I-IV disease. MCM7 LI>5% was associated with an increased risk of progression in stages I-V, I-III, and I-II. Our study confirms that MCM7 is a valuable marker for assessing the progression of PanNENs, especially in patients with early-stage disease and without distant metastasis.
- Endoscopic Resection of Duodenal Carcinoid Tumors: A Single-Center Comparison Between Simple Polypectomy and Endoscopic Mucosal Resection
Pancreas 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30451799
OBJECTIVES: Endoscopic resection is preferred for duodenal carcinoids less than 20 mm; however, the efficacy of simple polypectomy has not been compared with advanced endoscopic resection techniques. METHODS: We performed a retrospective review of 33 patients who underwent endoscopic duodenal carcinoid resection (10 simple, 23 endoscopic mucosal resection) at the Hospital of the University of Pennsylvania between January 1, 2006, and June 15, 2017. The primary outcomes were resection margin positivity and local tumor recurrence. RESULTS: There were no significant differences in demographics or tumor functionality. Lesions managed with simple polypectomy had smaller median gross specimen size (6.0 mm vs 8.0 mm, P = 0.043). There was no significant difference in pathology resection margins between simple polypectomy and endoscopic mucosal resection (86% vs 68% positive, P = 0.64). Local recurrence on surveillance endoscopy was also similar (14.3% vs 17.7%, respectively; P = 1.000), with median time to recurrence 2.3 months (interquartile range, 1.2-5.4 months). The median follow-up time in patients without local recurrence was 21.4 months (interquartile range, 7.1-39.6 months). CONCLUSIONS: Simple polypectomy may be adequate treatment of small duodenal carcinoids, although further studies are needed for validation and to define the upper limits of tumor size that can be managed with this technique.
- Proinsulin Expressing Neuroendocrine Tumors of the Pancreas: An Underrecognized Entity
Pancreas 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30451800
OBJECTIVES: Rare cases of pancreatic neuroendocrine tumors (PNETs) that produce only proinsulin (PI) and manifest with hypoglycemia have been reported. Proinsulin expression in PNET has not been systematically studied, and the clinicopathologic features of such tumors remain unknown. METHODS: We studied expression of PI by immunohistochemistry (IHC) in 136 PNETs from 2 high-volume surgical oncology centers and assessed all available clinicopathologic data. RESULTS: Thirty-six (26%) of PNETs were positive for PI by IHC, most (89%) of which coexpressed insulin IHC. Nine PI-positive tumors represented functional insulinomas. Patients with PI IHC-positive tumors demonstrated significantly lower mean preoperative serum glucose compared with PI-negative PNET patients, even when insulinomas were excluded. No differences in survival between PI IHC-positive and PI IHC-negative tumors were observed. We identified 2 PI-positive PNETs from hypoglycemic patients, which were not insulinomas or other functional variants and in which serum PI was never tested. These may have been undetected proinsulinomas. CONCLUSIONS: Proinsulin-expressing PNETs (functional or non) are not uncommon. Patients who present with hypoglycemia and normal insulin levels should be screened for proinsulinoma. Proinsulin IHC could also be used to screen for proinsulinoma. To further elucidate the clinical significance of PI expressing PNETs, prospective studies are required.
- High Minichromosome maintenance protein 7 proliferation indices: a powerful predictor of progression in pancreatic neuroendocrine neoplasms without distant metastasis at the time of surgery
https://www.sciencedirect.com/science/article/pii/S0046817718304258
- ASO Author Reflections: Redefining the Ki-67 Index Stratification for Low-Grade Pancreatic Neuroendocrine Tumors
Annals of surgical oncology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30456670
- Neuroendocrine Liver Metastasis-a Specific Set of Markers to Detect Primary Tumor Sites
Endocrine pathology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30456697
The diagnosis of neuroendocrine neoplasia (NEN) is often made at an advanced stage of disease, including hepatic metastasis. At this point, the primary may still be unknown and sometimes cannot even be detected by functional imaging, especially in very small tumors of the pancreas (pan) and small intestinal (si) entities. The site of the primary may be based on biopsy specimens of the liver applying a specific set of markers. Specimens of liver metastases from 87 patients with NENs were studied. In retrospect, 50 patients had si and 37 pan NENs. Tissue samples were evaluated by immunohistochemistry. The markers applied were insulin gene enhancer protein Islet-1 (ISL-1), homeobox protein CDX-2 (CDX2), thyroid transcription factor 1 (TTF-1), and serotonin. Positive stains for CDX2 were documented in 43 (86%) and for serotonin in 45 (90%) of 50 siNENs. Three panNENs were positive for CDX2 and one for serotonin, respectively. ISL-1 was negative throughout in siNENs and also negative in 8 of 50 panNENs (21.6%). TTF-1 was negative in more than 90% of the specimens of either entity. Immunohistochemical markers in liver metastasis can lead the way to the site of the primary NEN. They should always be used in combined clusters.
- Neuroendocrine Liver Metastasis—a Specific Set of Markers to Detect Primary Tumor Sites
https://link.springer.com/article/10.1007/s12022-018-9558-z
- Association between preoperative Vasostatin-1 and pathological features of aggressiveness in localized nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET)
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30470614
BACKGROUND: A reliable and accessible biomarker for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) is currently unavailable. Chromogranin A (CgA) represents the best-described neuroendocrine biomarker, but its accuracy is low. Vasostatin-1 (VS-1), a fragment derived from the cleavage of CgA, was recently investigated and found to be more accurate as tumor biomarker in a cohort of patients affected by mainly metastatic small intestinal NET. METHODS: Patients submitted to surgery for sporadic localized NF-PanNET at San Raffaele Hospital were included. Preoperative plasma samples were prospectively collected. Circulating levels of total-CgA and VS-1 were retrospectively investigated by sandwich Enzyme-Linked ImmunoSorbent Assays. RESULTS: Overall, 50 patients were included. VS-1 value (P=0.0001) was the only preoperatively retrievable factor independently associated with NF-PanNET size. No significant correlation between CgA and tumor diameter was found (P = 0.057). A VS-1 value of 0.39 nM was identified as the optimal VS-1 cut-off accurately associated with NF-PanNET larger than 4 cm. Patients with VS-1 > 0.39 nM had a significantly higher frequency of microvascular invasion (P = 0.005) and nodal metastasis (P = 0.027). Median VS-1 plasma level was significantly higher in the presence of microvascular invasion (P = 0.001) and nodal metastasis (P = 0.012). PPI assumption significantly increased total-CgA levels, but not those of VS-1 (P = 0.111). CONCLUSIONS: In localized, non-metastatic NF-PanNET, VS-1 is strongly associated to tumor dimension and its plasma levels are significantly higher in the presence of microvascular invasion and nodal metastases; moreover, VS-1 value is not affected by the PPI use.
- Duodenal gangliocytic paraganglioma: A rare cause for gastrointestinal polyp
Indian journal of pathology & microbiology 2018 10;61(4):580-582
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30303155
Duodenal gangliocytic paragangliomas are rare neoplasms often arising in the duodenum in close proximity to the ampulla of Vater. These neoplasms are considered to have a benign behavior with lymph node metastases being a rare phenomenon and distant metastases even more so. Although a standardized treatment has not been determined, a margin-free tumor resection seems to be the best treatment modality. We report herein the case of a 36-year-old female who presented with abdominal pain and was found to have a polyp in the second part of duodenum which was excised endoscopically. Histopathology and immunohistochemistry revealed characteristic features of this rare tumor.
- Unmet Needs in Functional and Nonfunctional pancreatic neuroendocrine neoplasms(PanNENs)
Neuroendocrinology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30282083
Recently, European Neuroendocrine Tumor Society (ENETS )held working sessions composed of members of the advisory board and other Neuroendocrine neoplasms (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This section briefly summarizes the main proposed areas of unmet needs in patients with functional and non-functional pancreatic neuroendocrine neoplasms (PanNENs).
- Immunohistochemical analysis of OTP and NKX6.1 in neuroendocrine tumors of the lung and pancreas
Diagnostic cytopathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30284410
BACKGROUND: Homeobox transcription factors have demonstrated utility in diagnosing neuroendocrine tumors. Orthopedia homeobox protein (OTP) has a well-defined role in embryonic neurodevelopment and has also been described as a prognostic marker in lung neuroendocrine tumors (NET). Additionally, NK6 homeobox-1 (NKX6.1) has been described to be necessary for the development of neuroendocrine cells in the pancreas. We evaluated immunohistochemical (IHC) expression of OTP and NKX6.1 to determine their utility in the diagnosis of NETs from lung and pancreas fine-needle aspirations (FNA). METHODS: Our study examined 50 FNA specimens, including 30 primary pulmonary NETs (8 carcinoid tumors (CT), 6 atypical carcinoids (AC), 11 small-cell neuroendocrine carcinomas (SCNEC), 5 large-cell neuroendocrine carcinomas (LCNEC)) and 20 primary pancreatic NETs (17 well-differentiated pancreatic neuroendocrine tumors (PanNET) and 3 poorly differentiated pancreatic neuroendocrine carcinomas (PanNEC)). IHC expression of OTP, NKX6.1, and Ki-67 was evaluated on FNA cell blocks. RESULTS: Half of the pulmonary TC tumors expressed OTP, while only 17% of AC and 20% of LCNEC expressed OTP. Neither SCNECs nor any pancreatic NET expressed OTP. In contrast, intermediate and high-grade tumors expressed NKX6.1 (LCNEC-80%, SCNEC-82%, and AC-83%) more often than low-grade tumors (TC-63%, PanNET-71%). All three PanNECs expressed NKX6.1. CONCLUSIONS: OTP may be useful in diagnosing well-differentiated NETs of pulmonary origin. NKX6.1 may have utility in segregating high from low-grade NETs of both pulmonary and pancreatic origin, although other methods will be required to determine site of origin.
- ASO Author Reflections: Contact Between T and N Classifications in Pancreatic Neuroendocrine Neoplasms
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30302639
- Symptomatic hepatic metastasis of insulinoma 15 years after pancreatic resection
Turkish journal of surgery 2018 01;34(3):240-242
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30302430
Malignant insulinomas are infrequent endocrine tumors with miscellaneous clinical courses. In this report, we present a rare case of insulinoma that recurred with solitary hepatic metastasis 15 years after the initial resection of the primary tumor from the pancreas. A 20-year-old woman first presented with the symptoms of hypoglycemia in 1996. The diagnosis of pancreatic insulinoma was confirmed by laboratory findings, and the initial surgery had been performed involving complete enucleation of the pancreatic mass. Histopathologically, the tumor was diagnosed as a benign adenoma. After 15 years, the patient experienced symptoms of hypoglycemia again, and laboratory findings and abdominal computed tomography identified a lesion in the liver. Intraoperative ultrasound did not show any lesion in the pancreas, and wedge resection was performed for the hepatic lesion. Postoperative blood glucose levels returned to normal. Histopathologic examination confirmed the diagnosis of liver metastasis of a neuroendocrine tumor. This is the longest interval between primary tumor and the metastasis reported in the literature, for insulinoma. Thus, it should be remembered that long-term follow-up is mandatory for the patients with insulinoma even after resection of the primary tumor. Resection is recommended when a metastatic lesion is observed.
- COMPETITIVE TESTING THE WHO 2010 VS THE WHO 2017 GRADING OF PANCREAS NEUROENDOCRINE NEOPLASIA: DATA FROM A LARGE INTERNATIONAL COHORT STUDY
Neuroendocrinology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30300897
Background: the World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tiers (WHO-AJCC 2010) to a four-tiers system by introducing the novel category of NET G3 (WHO-AJCC 2017). This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. 2102 patients were enrolled; entry criteria were i) performed surgery; ii) at least two years of follow-up; iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan Meier method, Cox regression analysis, Harrell’s C statistics and Royston’s explained variation in univariable and multivariable analyses. At descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. At Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS, however no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. At multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. the WHO-AJCC 2017 grading is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for patient survival prediction.
.
- ASO Author Reflections: Cytoreduction for Extrahepatic Metastatic Neuroendocrine Tumors
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30306370
- ASO Author Reflections: Recurrence Type of NEN Around the Head of the Pancreas
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315383
- ASO Author Reflections: Systemic Inflammatory Markers in Pancreatic Neuroendocrine Tumors
Annals of surgical oncology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30353397
Microenvironment
Neuroendocrine Tumor Stroma Interactions, Microenvironment, Inflammatory Response
- The epithelial-mesenchymal transition induces aggressivity of mucinous cystic neoplasm of the pancreas with neuroendocrine component: an immunohistochemistry study
https://www.sciencedirect.com/science/article/pii/S034403381831077X
Neuroendocrine Techniques & Research Methods
- Usefulness of indocyanine green‐fluorescence imaging for real‐time visualization of pancreas neuroendocrine tumor and cystic neoplasm
https://onlinelibrary.wiley.com/doi/10.1002/jso.25231
Cytopathology
Pancreas
- Abnormal Immunolabeling of SMAD4 in Cell Block Specimens Distinguish Malignant and Benign Pancreatic Cells
https://onlinelibrary.wiley.com/doi/abs/10.1111/cyt.12653
- Imaging and Cytopathological Criteria Indicating Malignancy in Mucin-Producing Pancreatic Neoplasms: A Series of 68 Histopathologically Confirmed Cases
Pancreas 2018 10;47(10):1283-1289
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30308535
OBJECTIVES: This study aims to evaluate the performance of clinical, imaging, and cytopathological criteria in the identification of high-grade dysplasia/carcinoma (HGD/Ca) in pancreatic mucin-producing cystic neoplasms. METHODS: Sixty-eight consecutive, histopathologically confirmed mucin-producing cystic neoplasms, evaluated by endoscopic ultrasound-guided fine-needle aspiration, were enrolled; specifically, 39 branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), 21 main duct IPMNs, and 8 mucinous cystic neoplasms. The associations between HGD/Ca in histopathology and findings of endoscopic ultrasound and cytology, demographic, lifestyle, and clinical parameters were evaluated, separately in IPMNs and mucinous cystic neoplasms. RESULTS: Age 65 years or more was associated with HGD/Ca in IPMNs. In BD-IPMNs, cyst diameter 3 cm or greater (sensitivity, 68.8%; specificity, 65.2%), a mural nodule (sensitivity, 56.3%; specificity, 78.3%), main pancreatic duct diameter 5 to 9 mm (sensitivity, 50.0%; specificity, 87.0%), and suspicious cytology (sensitivity, 81.3%; specificity, 100%) signaled the presence of HGD/Ca. Similarly, in main duct IPMNs, suspicious cytology predicted HGD/Ca with high sensitivity (88.9%) and excellent specificity (100%). Regarding cytopathological criteria, in BD-IPMNs, HGD/Ca was associated with a high nuclear/cytoplasmic ratio, background necrosis, presence of papillary structures, hypochromatic nuclei, hyperchromatic nuclei, and major nuclear membrane irregularities (thickening and/or indentations). CONCLUSIONS: Clinical, imaging, and cytopathological criteria are useful in the identification of HGD/Ca in IPMNs.
- EUS-Guided Enhanced Imaging and Sampling of Neoplastic Pancreatic Cysts
https://link.springer.com/chapter/10.1007/978-3-319-97376-0_12
- Pancreatic mixed acinar‐neuroendocrine carcinoma, a unique diagnostic challenge on FNA cytology: A small series of two cases with literature review
https://onlinelibrary.wiley.com/doi/abs/10.1002/dc.23981
- Histologic retrieval rate of a newly designed side-bevelled 20G needle for EUS-guided tissue acquisition of solid pancreatic lesions
http://journals.sagepub.com/doi/pdf/10.1177/2050640618804443
- Pancreaticobiliary cytopathology: an update
https://www.sciencedirect.com/science/article/pii/S1756231718301397
- Reclassification of lesions in biopsies by fine-needle aspiration of pancreas and biliary tree using Papanicolaou classification
http://jgo.amegroups.com/article/view/22469/html
- Abnormal Immunolabeling of SMAD4 in Cell Block Specimens Distinguish Malignant and Benign Pancreatic Cells
Cytopathology : official journal of the British Society for Clinical Cytology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30421464
BACKGROUND: Accurate diagnosis of malignant and benign pancreatic lesions can be challenging, especially in case of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples that are small and/or degraded. In the present study, we determined how to best evaluate abnormal SMAD4 expression by immunohistochemical staining on cell-block specimens from EUS-FNA samples. RESULTS: In surgically resected pancreas, when abnormal SMAD4 immunolabeling was evaluated as negative SMAD4 expression, the sensitivity was low (33%), but when it was evaluated as decreased SMAD4 expression, the sensitivity improved (53%). Specificity and positive predictive value were high for both evaluations. There were no false positive cases. In cell-block specimens, decreased SMAD4 expression showed 47% sensitivity and 72% specificity, while negative SMAD4 expression showed lower sensitivity (20%) and higher specificity (100%). Both evaluations in cell-block specimens showed lower sensitivity and specificity compared to the case for resected specimens. False positive and negative rates were higher for cell blocks than for resected specimens. CONCLUSIONS: Decreased SMAD4 immunolabeling provided improved sensitivity as compared to negative SMAD4 immunolabeling; therefore, it is important to compare SMAD4 expression in a sample to its expression in normal cells. Abnormal SMAD4 labeling showed low sensitivity and high specificity; therefore, SMAD4 staining using EUS-FNA samples might be helpful to detect malignancies that possess SMAD4 gene abnormalities. This article is protected by copyright. All rights reserved.
- Rationale and feasibility of mucin expression profiling by qRT-PCR as diagnostic biomarkers in cytology specimens of pancreatic cancer
https://www.sciencedirect.com/science/article/pii/S1424390318306859
- Papillary thyroid carcinoma metastatic to the pancreas: Case report
Diagnostic cytopathology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30479026
Papillary thyroid carcinoma (PTC) is generally associated with an excellent long-term outcome. Distant metastasis is rare with only 5-7% of patients developing distant disease. Metastasis of PTC to the pancreas is an exceedingly rare occurrence. To date, few cases have been reported. We present the case of an 81-year-old man with past medical history of PTC status post total thyroidectomy with local recurrence treated with radioactive iodine and selective neck dissection. Ten years after his initial diagnosis, PET-CT scan revealed a new hypermetabolic 1.1 cm × 0.9 cm left lower lobe lung nodule and hypermetabolism in the proximal body of the pancreas. Follow-up MRI cholangiogram showed a 1.0 × 0.8 cm T1 hypointense lesion in the proximal body of the pancreas. Endoscopic ultrasound-guided fine-needle aspiration biopsy of the pancreatic mass showed neoplastic epithelial cells arranged in papillary clusters with fibrovascular cores and syncytial sheets with high nuclear to cytoplasmic ratio, visible nucleoli, nuclear pallor, focal nuclear grooves, and rare intranuclear pseudoinclusions. Immunohistochemical stains performed on the smears showed positive nuclear expression of TTF-1 and PAX-8. The findings were consistent with metastatic PTC. Surgical resection of the lung nodule confirmed metastatic PTC. Pancreatic metastases usually occur after long time intervals with reports of up to 8 years in PTC. This makes the diagnosis more challenging, and metastatic disease should always be in the differential diagnosis in cases presenting with a pancreatic mass, especially in patients with a prior malignancy.
- Cytomorphology of ciliated foregut cyst of the pancreas
Diagnostic cytopathology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30478999
Ciliated foregut cysts are benign congenital lesions that are commonly found in the mediastinum but are rare in the retroperitoneum. So far only very few cases of ciliated foregut cyst found in the pancreas have been reported, and less with cytologic findings described. We report a case of ciliated foregut cyst in pancreas in an asymptomatic patient diagnosed on fine needle aspiration cytology. We also discuss the cytology features that would help with the diagnosis, and the differential diagnosis that should be considered.
- Rationale and feasibility of mucin expression profiling by qRT-PCR as diagnostic biomarkers in cytology specimens of pancreatic cancer
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;18(8):977-982
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30268674
BACKGROUND: Aberrantly expressed mucin glycoproteins (MUC) play important roles in pancreatic ductal adenocarcinoma (PDAC), yet their use as a diagnostic aid in fine-needle aspiration biopsy (FNAB) is poorly documented. The aim of this study was to investigate the rationale and feasibility of mucin (MUC1, MUC2, MUC3, MUC4, MUC5AC, and MUC6) expression profiling by RT-PCR for diagnostic applications in cytology. METHODS: Mucin expression was examined by RT-PCR and immunohistochemistry in specimens resected from patients with pancreatic (n = 101), ampullary (n = 23), and common bile duct (n = 10) cancers and 33 with chronic pancreatitis. Furthermore, mucin profiling by RT-PCR was prospectively compared in surgical and biopsy specimens of 40 patients with pancreatic solid tumours qualified for FNAB prior to surgery. RESULTS: A logistic regression model to distinguish PDAC from chronic pancreatitis using RT-PCR profiling included MUC3, MUC5AC, and MUC6. The same set of mucins differentiated ampullary and bile duct cancers from chronic pancreatitis. AUCs for the ROC curves derived from the two models were 0.95 (95%CI 0.87-0.99) and 0.92 (95%CI 0.81-0.98), respectively. The corresponding positive likelihood ratios were 6.02 and 5.97, while the negative likelihood ratios were 0.10 and 0.12. AUCs of ROC curves obtained by RT-PCR and immunohistochemistry demonstrated that both analytical methods were comparable. Surgical and cytological samples showed significantly correlated values of ΔCt for individual mucins with the overall Pearson’s correlation coefficient r = 0.841 (P = 0.001). CONCLUSIONS: Mucin expression profiling of pancreatic cancer with RT-PCR is feasible and may be a valuable help in discriminating malignant lesions from chronic pancreatitis in FNAB cytology.
- Pancreatic mixed acinar-neuroendocrine carcinoma, a unique diagnostic challenge on FNA cytology: A small series of two cases with literature review
Diagnostic cytopathology 2018 Nov;46(11):971-976
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30284406
Mixed acinar-neuroendocrine carcinoma (MANEC) of the pancreas is a rare tumor. We present two cases of MANEC diagnosed on endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA). The first patient is a 33-year-old male who had a 3.6 cm mass in the uncinate process and liver metastasis. The second patient is a 66-year-old male with a 10 cm mass in the pancreatic tail. The FNA smears from both cases were hypercellular with neoplastic cells in loosely cohesive clusters and many naked nuclei. In both cases, the tumor cells were positive for CKAE1/3, synaptophysin, chromogranin, and trypsin by immunohistochemistry. Final diagnoses of MANEC were rendered based on cytological features and immunohistochemical profiles. To date, 44 cases of MANEC have been reported in the English literature, only three of which were diagnosed on cytopathology specimens before surgical resection. Our report adds two more cases diagnosed on cytopathology alone. Herein, we discuss the various cytomorphologic and clinical features of MANEC and present a brief review of the literature. Diagn. Cytopathol.
- Towards optimal pancreatic cyst fluid management: the need for standardisation
Gut 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30301772
- INSM1 expression in pancreatic neuroendocrine tumors in endoscopic ultrasound-guided fine needle aspiration cytology: an analysis of 14 patients
Cytopathology : official journal of the British Society for Clinical Cytology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30290028
BACKGROUND: Insulinoma-associated protein 1 (INSM1) has been reported to be a useful marker for diagnosing pancreatic neuroendocrine tumors (PNETs). However, INSM1 expression in endoscopic ultrasound-fine needle aspiration cytology (EUS-FNAC) has not been examined. We evaluated INSM1 expression in the cytology of cases diagnosed with PNETs. METHODS: We immunocytochemically stained INSM1 and Ki-67 in 14 PNET cases, and according to the 2017 World Health Organization criteria, 7 PNET Grade 1 (G1) cases, 4 Grade 2 (G2) cases, and 3 Grade 3 (G3)/neuroendocrine carcinoma (NEC) cases were identified. As a control for INSM1 and Ki-67 expression, we used cytological specimens from 15 cases of pancreatic ductal adenocarcinoma (PDAC). RESULTS: In PNET cases, INSM1-expressing tumor cells were identified in all cytological specimens of PNET. The median INSM1 expression rate in G1 cases was 49.8% (mean±SD: 55.1±12.5%, min: 39.3%, max: 74.1%), and in G2 and G3/NEC cases was 81.1% (mean±SD: 77.6±18.6%, min: 50.3%, max: 100%). However, there was no correlation between INSM1 and Ki-67 expression (r= -0.15).The median expression rate in PNET cases was 64.3%, which was significantly higher than that in PDAC cases (p<0.0001). CONCLUSION: INSM1 immunocytochemistry of cytological specimens obtained from EUS-FNAC can accurately diagnose PNETs; therefore, INSM1 could be an important diagnostic tool in assessing therapeutic strategies, including molecular-targeted therapy. This article is protected by copyright. All rights reserved.
- Accuracy of grading pancreatic neuroendocrine neoplasms with Ki-67 index in fine-needle aspiration cellblock material
Cytopathology : official journal of the British Society for Clinical Cytology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30303569
OBJECTIVE: The aim of this study was to assess the preoperative tumour grade of pancreatic neuroendocrine neoplasms (panNENs) by determining the Ki-67 index in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) material and to correlate the preoperative tumour grade with the postoperative tumour grade in surgical specimens. METHODS: We performed a retrospective review of the institutional pathology database over a 10-year period (2007-2017) to identify all cases of panNENs with corresponding preoperative EUS-FNA cytological material and surgical specimens. Fifteen cases with adequate EUS-FNA material (more than 400 tumour cells on cellblock) were identified. The cytological and histological samples were graded based on the mitotic rate and the Ki-67 index in accordance with the 2017 World Health Organisation grading system for panNENs. The tumour grades determined on EUS-FNA cellblock material were compared with the histological tumour grades. RESULTS: Mean age at diagnosis was 64.8 ± 12.7 years (range, 38-85 years). The grading scores assigned to the cytological and histological samples were concordant in all 15 (100%) cases. Of those, two (13%) cases were scored as grade 1, nine (60%) cases as grade 2 and four (27%) cases as grade 3 tumours. CONCLUSION: Our study shows that tumour grade in patients with PanNENs can be reliably determined by assessing the Ki-67 index in EUS-FNA specimens based on the 2017 World Health Organisation classification and grading system.
- Endoscopic ultrasound-guided fine needle aspiration with liquid-based cytology preparation in the diagnosis of metastatic small-cell carcinoma in the pancreas
Diagnostic cytopathology 2018 Nov;46(11):977-980
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30353700
Pancreatic metastasis is extremely rare, particularly from small-cell lung cancer (SCLC). Studies on the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with liquid-based cytology (LBC) in the diagnosis of metastatic small-cell carcinoma in the pancreas have been rarely conducted. We report herein a case of pancreatic metastasis from SCLC diagnosed using EUS-FNA with LBC (ThinPrep). A 71-year-old man presented with chief complaints of hemoptysis and jaundice over the past 1 month. Lung & pancreas tumors with multiple liver nodules were detected on computed tomography. The aspirated material from the pancreas using EUS-FNA was prepared as a cytologic specimen with ThinPrep method, which revealed scattered and clustered “small blue cells” with scant cytoplasm and stippled chromatin with frequent apoptotic bodies. Immunocytochemical staining of the cellblock material revealed strong positivity for CD56 and thyroid transcription factor-1. Endobronchial biopsy for lung mass revealed nests of small, round, blue tumor cells with hyperchromatic nuclei showing salt and pepper chromatin, scant cytoplasm, and brisk mitotic activity. Therefore, a diagnosis of metastatic small-cell carcinoma to the pancreas with an extensive stage was finally made.
- Comparison of Native Aspirates and Cytological Smears Obtained by EUS-Guided Biopsies for Effective DNA/RNA Marker Testing in Pancreatic Cancer
Pathology oncology research : POR 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30361898
We compare two types of pancreatic carcinoma samples obtained by EUS-guided fine needle biopsy (EUS-FNB) in terms of the success rates and clinical validity of analysis of two most commonly investigated DNA/RNA pancreatic cancer markers, KRAS mutations and miR-21 expression. 118 patients with pancreatic ductal adenocarcinoma underwent EUS-FNB. The collected sample was divided, one part was stored in a stabilizing solution as native aspirate (EUS-FNA) and second part was processed into the cytological smear (EUS-FNC). DNA/RNA extraction was followed by analysis of KRAS mutations and miR-21 expression. For both sample types, the yields of DNA/RNA extraction and success rates of KRAS mutation and miRNA expression were evaluated. Finally, the resulting KRAS mutation frequency and miR-21 prognostic role were compared to literature data from tissue resections. The overall amount of isolated DNA/RNA from EUS-FNC was lower compared to the EUS-FNA, average yield 10 ng vs 147 ng for DNA and average yield 164 vs. 642 ng for RNA, but the success rates for KRAS and miR-21 analysis was 100% for both sample types. The KRAS-mutant detection frequency in EUS-FNC was 12% higher than in EUS-FNA (90 vs 78%). The prognostic role of miR-21 was confirmed in EUS-FNC (p = 0.02), but did not reach statistical significance in EUS-FNA (p = 0.06). Although both types of EUS-FNB samples are suitable for DNA/RNA extraction and subsequent DNA mutation and miRNA expression analysis, reliable results with clinical validity were only obtained for EUS-FNC.
Bile Ducts
- Molecular Diagnostics in Pancreatic and Biliary Cytology
https://link.springer.com/chapter/10.1007/978-3-319-97397-5_15
Gallbladder
- Mucinous adenocarcinoma of gallbladder: Subcategorisation on fine-needle aspiration cytology
Diagnostic cytopathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30375181
BACKGROUND: Mucinous adenocarcinoma (MC) of gallbladder is a rare histological subtype of gallbladder carcinoma (CaGB) which presents at an advanced stage and is associated with a poor prognosis compared to the conventional CaGB. This variant has been described mostly as reports or series, except for a single detailed histological and immunohistochemical analysis. Till date, there are no studies describing the cytomorphology of MC in detail. Hence, we undertook this study to analyse the cytomorphological features of MC. METHODS: A retrospective cytomorphological analysis was performed on MC identified out of all CaGB diagnosed on cytology over a period of last 4 years. The architectural and cellular features were recorded in a structured proforma. RESULTS: Thirty-three cases (33/987, 3.3%) were identified as MC. Extracellular mucin >90% was seen only in 3 cases whereas the remaining 30 had 50%-90% mucin. The predominant architectural pattern was tight epithelial fragments (14/33). The tumour cells were mostly of intermediate size (31/33) and had moderate amount of cytoplasm (31/33). Majority of the cases showed moderate nuclear pleomorphism (28/33) and nuclear chromatin was fine granular (17/33) or vesicular (14/33). Most of the cases had single and small nucleoli (26/33). Presence of inflammation composed predominantly of polymorphs was noted in 25 cases. Majority of the cases showed no (15/33) or scant necrosis (13/33). CONCLUSION: The morphological features of MC can very well be demonstrated on cytology. As they are associated with poor prognosis compared to conventional CaGB, cytopathologists should try to document the subtype.
Neuroendocrine
- Advances in the cytologic diagnosis of gastroenteropancreatic neuroendocrine neoplasms
https://onlinelibrary.wiley.com/doi/full/10.1002/cncy.22073
- Grading by the Ki-67 Labeling Index of Endoscopic Ultrasound-Guided Fine Needle Aspiration Biopsy Specimens of Pancreatic Neuroendocrine Tumors Can Be Underestimated
Pancreas 2018 9;47(10):1296-1303
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30211805
OBJECTIVES: There is an increasing need for grading with small endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) specimens for the proper diagnosis and therapy selection of patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, our understanding of EUS-FNAB specimen grading is limited compared with surgically resected specimens. METHODS: We retrospectively determined Ki-67 labeling index (LI) of 33 matched EUS-FNAB and surgically resected PanNETs with digital image analyzer. Pairwise grades between the matched biopsy and surgically resected PanNET specimens were compared. RESULTS: The mean Ki-67 LI was higher in surgically resected PanNET specimens (5.5%) than in biopsy specimens (3.2%; P = 0.022). There was moderate agreement between the Ki-67 LI grades when individually evaluated matched biopsy and resected specimen pairs were compared (κ value = 0.62; P < 0.0001). However, discordance was noted in 6 cases (18%), and all of them were either grade 2 or 3 in resected PanNETs. CONCLUSIONS: Although Ki-67 LI grading of EUS-FNAB specimens may be concordant with that of matched surgically resected specimens in a large proportion of the PanNET cases, Ki-67 LI grading of EUS-FNAB specimens should be carefully applied in clinical practice because of the possibility of grading underestimation with grade 2 to 3 PanNET cases.
- Accuracy of Grading Pancreatic Neuroendocrine Neoplasms with Ki‐67 Index in Fine‐Needle Aspiration Cellblock Material
https://onlinelibrary.wiley.com/doi/10.1111/cyt.12643
Molecular Pathology
Pancreas
- TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma
https://www.sciencedirect.com/science/article/pii/S2211124718316401
- Integrated whole genome microarray analysis and immunohistochemical assay identifies COL11A1, GJB2 and CTRL as predictive biomarkers for pancreatic cancer
https://cancerci.biomedcentral.com/articles/10.1186/s12935-018-0669-x
- Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway
https://www.nature.com/articles/s41388-018-0403-0
- Rab14 overexpression regulates gemcitabine sensitivity through regulation of Bcl-2 and mitochondrial function in pancreatic cancer
Virchows Archiv : an international journal of pathology 2018 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30267303
Rab family protein Rab14 has been implicated in the development of human cancers. To date, its expression pattern, biological function, and potential mechanism in pancreatic cancer have not been explored. In this study, we analyzed Rab14 expression in 103 cases of pancreatic cancer tissues using immunohistochemistry (IHC) and found that Rab14 was overexpressed in 41/103 cases (39.8%). Rab14 overexpression correlated with the advanced stage. Moreover, elevated Rab14 levels indicated poor prognosis of patients with pancreatic cancers. We used BxPC-3 and Capan-2 respectively for plasmid and siRNA transfection. MTT and colony formation assays showed that Rab14 transfection increased cell proliferation and colony formation in BxPC-3 cells. Rab14 siRNA knockdown inhibits proliferation and colony formation ability in Capan-2 cell line. Cell cycle analysis showed that Rab14 facilitated cell cycle progression. Matrigel invasion assay showed that Rab14 promoted BxPC-3 cell invasion while its depletion inhibited Capan-2 cell invasion. In addition, MTT and AnnexinV/PI analysis demonstrated that overexpression of Rab14 reduced gemcitabine sensitivity which conversely was increased by Rab14 knockdown. We also demonstrated that Rab14 upregulated mitochondrial membrane potential (MMP) while its depletion downregulated MMP during gemcitabine treatment. In addition, western blotting revealed that Rab14 overexpression upregulated cyclin D1, cyclin A, cyclin E, p-Rb, and Bcl-2 and downregulated p21. Rab14 also downregulated caspase3, PARP cleavage, and cytochrome c release. In conclusion, our data indicated that Rab14 was overexpressed in pancreatic cancer and promotes growth and gemcitabine resistance, possibly through regulation of mitochondrial function and Bcl-2.
- Mast cells and angiogenesis in pancreatic ductal adenocarcinoma
Clinical and experimental medicine 2018 Aug;18(3):319-323
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29492715
Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase. The disruption of this pro-angiogenic and proliferative stimulation by inhibiting the mast cells migration and degranulation is under investigation as a potential therapeutic approach in pancreatic ductal adenocarcinoma patients. This review will summarize the literature concerning the mast cells infiltration in the pancreatic ductal adenocarcinoma analyzing its role in angiogenesis and tumor progression.
- Identification of a 5‑microRNA signature and hub miRNA‑mRNA interactions associated with pancreatic cancer
Oncology reports 2019 Jan;41(1):292-300
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30365134
miRNA‑gene axes have been reported to serve an important role in the carcinogenesis of pancreatic cancer (PC). The aim of the present study was to systematically identity the microRNA signature and hub molecules, as well as hub miRNA‑gene axes, and to explore the potential biomarkers and mechanisms associated with the carcinogenesis of PC. Eleven microRNA profile datasets were obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) and ArrayExpress databases, and a meta‑analysis was performed to identify the differentially expressed miRNAs (DEMs) between tumor tissue and normal tissue. Subsequently, a diagnostic regression model was constructed to identify PC based on The Cancer Genome Atlas (TCGA) miRNA sequence data by using the least absolute shrinkage and selection operator (LASSO) method. In addition, GSE41368 was downloaded, and a weighted gene co‑expression network analysis (WGCNA) was performed to obtain the gene module associated with carcinogenesis by using the TCGAbiolinks and WGCNA packages, respectively. Finally, miRNA‑gene networks were constructed and visualized using Cytoscape software, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses based on the Database for Annotation, Visualization, and Integrated Discovery (DAVID). A total of 14 DEMs were identified, and a 5‑microRNA‑based score generated by the LASSO regression model provided a high accuracy for identifying PC [area under the curve (AUC)=0.918]. In addition, 44 miRNA‑mRNA interactions were constructed, and 4 hub genes were screened on the basis of the above bioinformatic tools and databases. Furthermore, 14 biological process (BP) functions and 6 KEGG pathways were identified according to gene set enrichment analysis (GSEA). In summary, the present study applied integrated bioinformatics approaches to generate a holistic view of PC, thereby providing a basis for further clinical application of the 5‑miRNA signature and the identified hub molecules, as well as the miRNA‑gene axes, which could serve as diagnostic markers and potential treatment targets.
- Assessing The Predictive Value Of Regulatory Molecules For Patient Outcome In Pancreatic Cancer: A Computational Approach
https://ieeexplore.ieee.org/abstract/document/8512477
- Genetic Drivers of Pancreatic Cancer Are Identical Between the Primary Tumor and a Secondary Lesion in a Long-Term (>5 Years) Survivor After a Whipple Procedure
https://www.liebertpub.com/doi/abs/10.1089/pancan.2018.0015
- Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine
https://gut.bmj.com/content/early/2018/11/05/gutjnl-2018-316822
- The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer
https://www.nature.com/articles/s41388-018-0553-0
- The Long Noncoding RNA HOST2 Promotes Gemcitabine Resistance in Human Pancreatic Cancer Cells
Pathology oncology research : POR 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30406400
Our study was aimed to identify the fundamental role of lncRNA HOST2 in gemcitabine resistance regulation in human pancreatic cancer cells. The levels of HOST2 in pancreatic cancer cell lines were measured by quantitative real-time PCR (qRT-PCR). Due to high expression and strong gemcitabine resistance, Hs766T and AsPC-1 cell lines were selected to be knockdown the expression of HOST2 by transfection sh-HOST2. After manipulation of HOST2, the cell proliferation induced by gemcitabine was examined by CCK-8 assay. Next, colony formation ability of Hs766T and AsPC-1 cell lines was determined by clone-forming assay. At last, the relationship between HOST2 and cell apoptosis in Hs766T and AsPC-1 cell lines was evaluated by flow cytometry. QRT-PCR revealed that HOST2 was overexpressed in six pancreas neoplasm cell lines compared with normal cell lines HPDE6-C7. HOST2 expression levels in group resistant to gemcitabine were higher than the group sensitive to gemcitabine. Additionally, CCK-8 assay verified that cell proliferation was inhibited by sh-HOST2 with or without gemcitabine treatment. Furthermore, clone-forming assay revealed that colony formation ability was weakened by down-regulated HOST2 with or without gemcitabine treatment. Flow cytometry revealed that cell apoptosis induced by gemcitabine was promoted by sh-HOST2. In conclusion, down-regulated HOST2 inhibited proliferation and promoted apoptosis of pancreas cancer cells with or without gemcitabine treatment. Thus, HOST2 is a potential therapeutic target for gemcitabine chemoresistance in pancreatic neoplasms.
- Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP
https://www.sciencedirect.com/science/article/pii/S2211124718316000
- Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion
https://www.nature.com/articles/s41467-018-07130-z
- Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer cell spread via extracellular signal-regulated kinase 2
https://www.sciencedirect.com/science/article/pii/S0945053X18302841
- Epigenetic Targeting DNMT1 of Pancreatic Ductal Adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through Hedgehog pathway inhibition
https://www.sciencedirect.com/science/article/pii/S1043661818306947
- IL-1-induced JAK/STAT signaling is antagonized by TGF-ß to shape CAF heterogeneity in pancreatic ductal adenocarcinoma
- Therapeutic potential of targeting the Wnt/β‐catenin pathway in the treatment of pancreatic cancer
https://onlinelibrary.wiley.com/doi/abs/10.1002/jcb.27835
- Desumoylating Isopeptidase 2 (DESI2) Inhibits Proliferation and Promotes Apoptosis of Pancreatic Cancer Cells through Regulating PI3K/AKT/mTOR Signaling Pathway
Pathology oncology research : POR 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30411297
This study aimed to investigate the effects of desumoylating isopeptidase 2 (DESI2) on tumor cell proliferation, apoptosis and invasion of pancreatic cancer, and to assess the signaling pathway involved. Overexpression and silence of DESI2 were designed and the experiments were divided into 5 groups: a normal control group, an interference control group (shRNA-NC); an interference group (sh-DESI2); an overexpression control group (NC), an overexpression group (DESI2). Quantitative real time polymerase chain reaction (qRT-PCR) was used to screen the appropriate interference sequence. The silencing and overexpression of DESI2 were confirmed by qRT-PCR and western blotting. Cell cycling, apoptosis, invasion, and the expression of phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway and caspase 3 were measured. Overexpression and silence of DESI2 were successfully designed in two pancreatic cancer cells, and the interference effect of sh-DESI2-3 showed the best silencing effects. The biological activities of DESI2 were detected in both ASPC-1 and PANCE-1 cells. Our results showed that cell proliferation was significantly increased in the sh-DESI2 group, while decreased in DESI2 group compared with the control group in both cell lines. In ASPC-1 cells, the events in G1 phase decreased and in S phase increased obviously in the sh-DESI2 group, compared with control group. An opposite result was found when DESI2 was overexpressed. In PANCE-1 cells, the events in G2 phase were higher in the sh-DESI2 group, while in the DESI2 group was significantly lower than that in control group. In ASPC-1 and PANCE-1 cells, sh-DESI2 group showed decreased apoptosis, increased cell invasion and increased expression of AKT, p-Akt, PI3K, p-PI3K, p-mTOR and mTOR and decreased caspase 3 expression compared with the control group, while overexpression of DESI2 leaded to increased apoptosis, decreased cell invasion and reduced expression of AKT, p-Akt, PI3K, p-PI3K, p-mTOR and mTOR and increased expression of caspase 3. DESI2 regulates the proliferation and apoptosis of pancreatic cancer cells through PI3K/AKT/mTOR signaling pathway.
PIN1 maintains redox balance via the c-Myc/NRF2 axis to counteract Kras-induced mitochondrial respiratory injury in pancreatic cancer cells
http://cancerres.aacrjournals.org/content/canres/early/2018/10/24/0008-5472.CAN-18-1968.full.pdf
Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth
http://www.life-science-alliance.org/content/1/5/e201800190
Subcutaneous Inoculation of 3D Pancreatic Cancer Spheroids Results in Development of Reproducible Stroma-Rich Tumors
https://www.sciencedirect.com/science/article/pii/S1936523318304121
- Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms
https://academic.oup.com/jnci/article-abstract/110/10/1067/4915401?redirectedFrom=fulltext
- MicroRNA therapeutics: design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells
https://www.tandfonline.com/doi/full/10.1080/15476286.2018.1526536
- Referral frequency, attrition rate, and outcomes of germline testing in patients with pancreatic adenocarcinoma
https://link.springer.com/article/10.1007/s10689-018-0106-2
- Metastasis and chemoresistance in CD133 expressing pancreatic cancer cells are dependent on their lipid raft integrity
https://www.sciencedirect.com/science/article/pii/S0304383518305949
- Response of germline BRCA2-mutated advanced pancreatic acinar cell carcinoma to olaparib
- Targeting Purinergic Receptor P2Y2 prevents the growth of pancreatic ductal adenocarcinoma by inhibiting cancer cell glycolysis
http://clincancerres.aacrjournals.org/content/early/2018/11/10/1078-0432.CCR-18-2297?papetoc=
- SRC-3 Inhibition Blocks Tumor Growth of Pancreatic Ductal Adenocarcinoma
https://www.sciencedirect.com/science/article/pii/S0304383518306761
- Targeting integrin-linked kinase to suppress oncogenic KRAS signaling in pancreatic cancer
Small GTPases 2018 11;9(6):452-456
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=27936345
Although oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, it is deemed “non-druggable” because of the intrinsic difficulty in designing direct inhibitors of KRAS. Our recent work demonstrated a KRAS-integrin-linked kinase (ILK) regulatory feedback loop that allows pancreatic cancer cells to regulate KRAS expression and to interact with the tumor microenvironment to promote aggressive phenotype. KRAS induces E2F1-mediated transcriptional activation of ILK expression, and ILK, in turn, controls KRAS expression via hnRNPA1, which binds and destabilizes the G-quadruplex in the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven EMT and growth factor-stimulated KRAS expression. This regulatory loop, however, was not noted in KRAS mutant colorectal and lung cancer cells examined as knockdown of KRAS or ILK did not affect each other’s expression, suggesting that this KRAS-ILK feedback regulation is specific for pancreatic cancer. In sum, this regulatory loop provides a strong mechanistic rationale for suppressing oncogenic KRAS signaling through targeting ILK, and this creating a potential new therapeutic strategy for pancreatic cancer.
- p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation
World journal of gastroenterology 2018 Sep;24(33):3709-3723
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30197477
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
- Claudin 7 as a possible novel molecular target for the treatment of pancreatic cancer
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30416041
BACKGROUND/OBJECTIVES: Pancreatic cancer consists of various subpopulations of cells, some of which have aggressive proliferative properties. The molecules responsible for the aggressive proliferation of pancreatic cancer may become molecular targets for the therapies against pancreatic cancer. METHODS: From a human pancreatic cancer cell line, MIA PaCa-2, MIA PaCa-2-A cells with an epithelial morphology and MIA PaCa-2-R cells with a non-epithelial morphology were clonogenically isolated by the limiting dilution method. Gene expression of these subpopulations was analyzed by DNA microarray. Gene knockdown was performed using siRNA. RESULTS: Although the MIA PaCa-2-A and MIA PaCa-2-R cells displayed the same DNA short tandem repeat (STR) pattern identical to that of the parental MIA PaCa-2 cells, the MIA PaCa-2-A cells were more proliferative than the MIA PaCa-2-R cells both in culture and in tumor xenografts generated in immunodeficient mice. Furthermore, the MIA PaCa-2-A cells were more resistant to gemcitabine than the MIA PaCa-2-R cells. DNA microarray analysis revealed a high expression of claudin (CLDN) 7 in the MIA PaCa-2-A cells, as opposed to a low expression in the MIA PaCa-2-R cells. The knockdown of CLDN7 in the MIA PaCa-2-A cells induced a marked inhibition of proliferation. The MIA PaCa-2-A cells in which CLDN7 was knocked down exhibited a decreased expression of phosphorylated extracellular signal-regulated kinase (p-Erk)1/2 and G1 cell cycle arrest. CONCLUSIONS: CLDN7 may be expressed in the rapidly proliferating and dominant cell population in human pancreatic cancer tissues and may be a novel molecular target for the treatment of pancreatic cancer.
- H19 long non-coding RNA contributes to sphere formation and invasion through regulation of CD24 and integrin expression in pancreatic cancer cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205177/
- Impact of Ethnicity on Somatic Mutation Rates of Pancreatic Adenocarcinoma
http://iv.iiarjournals.org/content/32/6/1527.full
- Integrated whole genome microarray analysis and immunohistochemical assay identifies COL11A1, GJB2 and CTRL as predictive biomarkers for pancreatic cancer
Cancer cell international 2018 11;18():174
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30410422
Background: Pancreatic cancer is characterized by its unsatisfying early detection rate, rapid disease progression and poor prognosis. Further studies on molecular mechanism and novel predictive biomarkers for pancreatic cancer based on a large sample volume are required. Methods: Multiple bioinformatic analysis tools were utilized for identification and characterization of differentially expressed genes (DEGs) from a merged microarray data (100 pancreatic cancer samples and 62 normal samples). Data from the GEO and TCGA database was utilized to validate the diagnostic and prognostic value of the top 5 upregulated/downregulated DEGs. Immunohistochemical assay (46 paired pancreatic and para- cancerous samples) was utilized to validate the expression and prognostic value of COL11A1, GJB2 and CTRL from the identified DEGs. Results: A total number of 300 DEGs were identified from the merged microarray data of 100 pancreatic cancer samples and 62 normal samples. These DEGs were closely correlated with the biological characteristics of pancreatic cancer. The top 5 upregulated/downregulated DEGs showed good individual diagnostic/prognostic value and better combined diagnostic/prognostic value. Validation of COL11A1, GJB2 and CTRL with immunohistochemical assay showed consistent expression level with bioinformatics analysis and promising prognostic value. Conclusions: Merged microarray data with bigger sample volume could reflect the biological characteristics of pancreatic cancer more effectively and accurately. COL11A1, GJB2 and CTRL are novel predictive biomarkers for pancreatic cancer.
- Identification of hub genes with diagnostic values in pancreatic cancer by bioinformatics analyses and supervised learning methods
World journal of surgical oncology 2018 Nov;16(1):223
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30428899
BACKGROUND: Pancreatic cancer is one of the most lethal tumors with poor prognosis, and lacks of effective biomarkers in diagnosis and treatment. The aim of this investigation was to identify hub genes in pancreatic cancer, which would serve as potential biomarkers for cancer diagnosis and therapy in the future. METHODS: Combination of two expression profiles of GSE16515 and GSE22780 from Gene Expression Omnibus (GEO) database was served as training set. Differentially expressed genes (DEGs) with top 25% variance followed by protein-protein interaction (PPI) network were performed to find candidate genes. Then, hub genes were further screened by survival and cox analyses in The Cancer Genome Atlas (TCGA) database. Finally, hub genes were validated in GSE15471 dataset from GEO by supervised learning methods k-nearest neighbor (kNN) and random forest algorithms. RESULTS: After quality control and batch effect elimination of training set, 181 DEGs bearing top 25% variance were identified as candidate genes. Then, two hub genes, MMP7 and ITGA2, correlating with diagnosis and prognosis of pancreatic cancer were screened as hub genes according to above-mentioned bioinformatics methods. Finally, hub genes were demonstrated to successfully differ tumor samples from normal tissues with predictive accuracies reached to 93.59 and 81.31% by using kNN and random forest algorithms, respectively. CONCLUSIONS: All the hub genes were associated with the regulation of tumor microenvironment, which implicated in tumor proliferation, progression, migration, and metastasis. Our results provide a novel prospect for diagnosis and treatment of pancreatic cancer, which may have a further application in clinical.
- Chemoresistance Transmission via Exosome-Mediated EphA2 Transfer in Pancreatic Cancer
http://www.thno.org/v08p5986.pdf
-SWI/SNF component ARID1A restrains pancreatic neoplasia formation
https://gut.bmj.com/content/early/2018/10/12/gutjnl-2017-315490
- Small molecule tyrosine kinase inhibitors and pancreatic cancer—Trials and troubles
https://www.sciencedirect.com/science/article/pii/S1044579X18301342
- Higher notch expression implies poor survival in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis
https://www.sciencedirect.com/science/article/pii/S1424390318306914
- Combination treatment of advanced pancreatic cancer using novel vaccine and traditional therapies
https://www.tandfonline.com/doi/abs/10.1080/14737140.2018.1531707
- Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma
- DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth
https://gut.bmj.com/content/early/2018/10/20/gutjnl-2018-316128
- Identification of hub genes with diagnostic values in pancreatic cancer by bioinformatics analyses and supervised learning methods
https://wjso.biomedcentral.com/articles/10.1186/s12957-018-1519-y
- miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1
https://www.karger.com/Article/PDF/495328
- Atg5 in pancreatic tumorigenesis and progression: dosage matters
Gastroenterology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30472231
- New Horizons in the Treatment of Metastatic Pancreatic Cancer: A Review of the Key Biology Features and the Most Recent Advances to Treat Metastatic Pancreatic Cancer
https://link.springer.com/article/10.1007/s11523-018-0609-7
- LncRNA H19/miR-194/PFTK1 axis modulates the cell proliferation and migration of pancreatic cancer
Journal of cellular biochemistry 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30474270
Pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge due to its high mortality and morbidity; gene therapy might be a promising treatment for PDAC. The critical role of Wnt-signaling pathway in cancer pathogenesis has been widely recognized; cyclin-dependent kinase 14 (CDK14, PFTK1)-induced low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) phosphorylation is an important issue in Wnt-signaling activation. Long noncoding RNA (LncRNA)-microRNA (miRNA)-messenger RNA (mRNA) modulating the pathogenesis of cancers has been regarded as a major mechanism. In the current study, upregulated lncRNAs positively correlated with PFTK1 were analyzed and selected using The Cancer Genome Atlas (TCGA) database. Of them, lncRNA H19 can activate Wnt signaling in cancers. In PDAC tissues, the expression of H19 and PFTK1 were upregulated; H19 knockdown suppressed the cell proliferation and migration of PDAC, while PFTK1 overexpression partially attenuated the suppressive effect of H19 knockdown. As analyzed by TCGA and predicted by online tools, miR-194 was negatively correlated with PFTK1 and might bind to both H19 and PFTK1, which was further confirmed by luciferase reporter and RNA immunoprecipitation assays. Moreover, the effect of H19 knockdown on PFTK1 protein and the cell proliferation and migration could be partially reversed by miR-194 inhibition; H19/miR-194 axis modulated PDAC cell proliferation and migration through PFTK1 downstream Wnt signaling. Results suggested that rescuing miR-194 expression in PDAC can inhibit lncRNA H19 and PFTK1 expression, subsequently suppressing PDAC cell proliferation and migration. Due to the complexity of the lncRNA-miRNA-mRNA network, further in vivo experiments examining potential side effects are needed in future study to explore the clinical application of these findings.
- Preprogramming therapeutic response of PI3K/mTOR dual inhibitor via the regulation of EHMT2 and p27 in pancreatic cancer
American journal of cancer research 2018 09;8(9):1812-1822
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30323973
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease, which is characterized by its high invasiveness, rapid progression, and profound resistance to therapy. Gemcitabine is the first-line treatment option for pancreatic cancer patients, but the overall survival is quite low. Therefore, it is an urgent issue to identify new molecules for improved therapies, with better efficacy and less toxicity. Our previous data indicated that Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) functions as a therapeutic target to override GEM resistance and promote metastasis in the treatment of pancreatic cancer. Here, we screened a small-molecule library of 143 protein kinase inhibitors, to verify cytotoxicity of different inhibitors in EHMT2-depleted cells. We determined that the EHMT2 plays a promising modulating role for targeted PI3K/mTOR inhibition. Our data revealed that EHMT2 down-regulates p27 expression, and this contributes to tumor growth. The depletion of EHMT2, ectopic expression of methyltransferase-dead EHMT2, or treatment with an EHMT2 inhibitor decreases H3K9 methylation of p27 promoter and induces G1 arrest in PANC-1 pancreatic cancer cells. Consistent with these findings, in vivo tumor xenograft models, primary tumors, and the Oncomine database utilizing bioinformatics approaches, also show a negative correlation between EHMT2 and p27. We further demonstrated that low EHMT2 elevated BEZ235 sensitivity through up-regulation of p27 in PDAC cells; high levels of SKP2 decrease BEZ235 responsiveness in PDAC cells. Altogether, our results suggest the EHMT2-p27 axis as a potential marker to modulate cell response to dual PI3K/mTOR inhibition, which might provide a strategy in personalized therapeutics for PDAC patients.
- Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma
Oncology research and treatment 2018 09;41(10):619-625
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30286473
Pancreatic cancer is one of the most common causes of cancer-related mortality in the Western world and pancreatic ductal adenocarcinoma (PDAC) is by far the most common pancreatic cancer entity. Locally advanced or metastatic PDAC remains a major clinical challenge, and the prognosis of affected patients is dismal despite substantial research efforts in this area. Recent large-scale genomic analyses of PDAC revealed that KRAS is the most frequently mutated driver gene in this entity. In addition, a relatively large proportion of PDAC patients displays germline variants in genes involved in DNA repair, particularly DNA double-strand repair. Similarly, a sizable fraction of sporadic PDAC cases harbor mutations in genome maintenance genes, such as BRCA1, BRCA2, and ATM. While direct targeting of oncogenic KRAS is currently not possible in the clinical setting, these defects in DNA repair may open new therapeutic avenues. Here, we discuss the potential use of compounds that interfere with DNA repair and genome maintenance mechanisms for the treatment of PDAC. We particularly focus on the genotype-tailored use of compounds, such as PARP inhibitors, as well as ATR- and DNA-protein kinase catalytic subunit (PKcs) inhibitors.
- Higher notch expression implies poor survival in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;18(8):954-961
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30297095
BACKGROUND: At present, pancreatic ductal adenocarcinoma (PDAC) is a fetal disease lack of effective prognostic and therapeutic methods resulting in high mortality. The Notch signaling has been demonstrated being up- or down-regulated in many cancers, but the effects in pancreatic ductal adenocarcinoma are still controversial. Moreover, the available cases in an individual study are of small samples. Therefore, it is essential to define the effect of Notch signaling in pancreatic ductal adenocarcinoma with larger samples. METHODS: Conducted from 6 eligible studies and 463 pancreatic ductal adenocarcinoma patients, this was the first meta-analysis to analyze the correlation between the Notch signal pathway and pancreatic ductal adenocarcinoma. All data were sourced from The National Center for Biotechnology Information, Web of Science and Cochrane. The articles which matched the inclusion criteria were included. All included data were analyzed and performed by Review Manager 5.3. RESULTS: The results indicated that high expression of Notch signaling proteins was associated with poor overall survival of pancreatic ductal adenocarcinoma patients (pooled hazard ratio>2.00; P < 0.001). Moreover, poor survival was related to high expression of Notch3 (pooled hazard ratio: 2.05; confidence interval: 1.49-2.82; P < 0.001) and DLL4 (pooled hazard ratio: 2.13; confidence interval: 1.37-3.32; P < 0.001). CONCLUSIONS: This meta-analysis supports that Notch signaling proteins may be available as prognostic factors for pancreatic ductal adenocarcinoma progression and patient survival. Higher expression of Notch signaling proteins indicated poor survival of pancreatic ductal adenocarcinoma patients. Targeting Notch signaling components, especially Notch3 protein, would be beneficial for therapies.
- SNX6 predicts poor prognosis and contributes to the metastasis of pancreatic cancer cells via activating epithelial-mesenchymal transition
Acta biochimica et biophysica Sinica 2018 Nov;50(11):1075-1084
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30307473
Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate around 6%. Though significant progress has been made in the availability of diagnostic techniques and treatment strategies, pancreatic cancer remains a disease of high mortality rate. Therefore, there is an urgent need for a better understanding of the molecular mechanisms that governs the oncogenesis and metastasis process of pancreatic cancer. In the present study, by using the Cancer Genome Atlas (TCGA) dataset analysis, we demonstrated that sorting nexin 6 (SNX6) serves as a biomarker for predicting prognosis of pancreatic cancer. In vitro studies demonstrated that silencing of SNX6 expression reduced cell proliferation, colony formation, invasion, and metastasis. Higher level of SNX6 helps maintain the mesenchymal properties, which renders migration and invasive capacities to pancreatic cancer cells. Moreover, in the process of TGF-β-induced epithelial to mesenchymal transition (EMT), the expression level of SNX6 was increased, and silencing of SNX6 expression could inhibit the TGF-β-induced EMT program. These results collectively uncovered a novel predictive marker for pancreatic cancer and provided the possible underlying molecular mechanism.
- Identification of key microRNAs and their targets in exosomes of pancreatic cancer using bioinformatics analysis
Medicine 2018 Sep;97(39):e12632
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30278585
Pancreatic cancer (PC) is one of the most lethal tumors, due to late diagnosis and limited surgical strategies. It has been reported that serum exosomal microRNAs (S-Exo-miRNAs) play a pivotal role as signaling molecules and serve as noninvasive diagnosis methods for PC. The combination of S-Exo-miRNAs with the corresponding target also plays an important role in the tumor microenvironment.Here we investigated S-Exo-miRNAs involved in PC. The gene expression profile was downloaded from the Gene Expression Omnibus (GEO) database. The analysis was carried out using GEO2R. The targets of differentially expressed serum exosomal miRNAs (DE-S-Exo-miRNAs) were predicted by 4 bioinformatic algorithms (miRanda, miRDB, miRWalk, and Targetscan). Further analysis with gene ontology (GO) and Kyoto Encyclopedia of Genomes pathway (KEGG) enrichment analyses were performed with Cytoscape software version 3.4.0. Subsequently, the interaction regulatory network of target genes was performed with the Search Tool for the Retrieval of Interacting Genes (STRING) database (http://www.string-db.org/) and visualized using Cytoscape software.We downloaded the gene expression profile GSE50632, which was based on an Agilent microarray GPL17660 platform containing 4 eligible samples. In total 467 DE-S-Exo-miRNAs were obtained, including 7 overexpressed miRNAs (1.50%), and 460 remaining underexpressed miRNAs (98.50%). The databases miRWalk, miRDB, miRanda, and TargetScan were used to predict their potential targets, which were subsequently submitted to Cytoscape software version 3.4.0 (www.cytoscape.org). Next the functional and pathway enrichment analysis were used for the KEGG pathway and GO categories analysis. The enrichment analysis identified the genes involved in such processes as developmental and negative regulation of multicellular organismal processes, regulation of anatomical structure morphogenesis, regulation of cell death, apoptotic processes and mitogen-activated protein kinase (MAPK) signaling pathway, transforming growth factor - beta (TGF -β) signaling pathway, cyclic adenosine monophosphate (cAMP) signaling pathway, and the phosphatidylinositol-3 kinases/Akt (PI3K-Akt) signaling pathway. Subsequently according to the protein-protein interaction (PPI) network, the top 10 genes were obtained. The enrichment analyses of the genes involved in a significant module revealed that these genes were related to the TGF-β signaling pathway. After reviewing the literature, we identified the apoptosis genes, and their corresponding miRNAs that have a relationship with apoptosis of the tumor.This analysis provides a comprehensive understanding of the roles of S-Exo-miRNAs and the related targets in the development of PC. Additionally, the present study provides promising candidate targets for early diagnosis and therapeutic intervention. However, these predictions require further experimental validation in future studies.
- Transcriptome-wide association study identifies multiple genes and pathways associated with pancreatic cancer
Cancer medicine 2018 Nov;7(11):5727-5732
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30334361
AIM: To identify novel candidate genes for pancreatic cancer. METHODS: We performed a transcriptome-wide association study (TWAS) analysis of pancreatic cancer (PC). GWAS summary data were driven from the published studies of PC, totally involving 558 542 SNPs in 1896 individuals with pancreatic cancer and 1939 healthy controls. FUSION software was applied to the PC GWAS summary data for tissue-related TWAS analysis, including whole blood, peripheral blood, adipose, and pancreas. The functional relevance of identified genes with PC was further validated by Oncomine, STRING, and CluePedia tool. RESULTS: Transcriptome-wide association study analysis identified 19 genes significantly associated with PC, such as LRP5L (P value = 5.21 × 10-5 ), SOX4 (P value = 3.2 × 10-4 ), and EGLN3 (P value = 6.2 × 10-3 ). KEGG pathway enrichment analysis detected several PC-associated pathways, such as One carbon pool by folate (P value = 1.60 × 10-16 ), Cell cycle (P value = 1.27 × 10-7 ), TGF-beta signaling pathway (P value = 4.64 × 10-6 ). Further comparing the 19 genes with previously identified overexpressed genes in PC patients found one overlapped gene SOX4. CONCLUSION: We identified some novel candidate genes and pathways associated with PC. Our results provide novel clues for the genetic mechanism studies of pancreatic cancer.
- Gene expression analysis of embryonic pancreas development master regulators and terminal cell fate markers in resected pancreatic cancer: A correlation with clinical outcome
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;18(8):945-953
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30293872
BACKGROUND: Despite the recent introduction of new drugs and the development of innovative multi-target treatments, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. Even when PDAC is resectable, the rate of local or widespread disease recurrence remains particularly high. Currently, reliable prognostic biomarkers of recurrence are lacking. We decided to explore the potential usefulness of pancreatic developmental regulators as biomarkers of PDAC relapse. METHODS: We analyzed by quantitative real-time PCR the mRNA of selected factors involved either in pancreatic organogenesis (ISL1, NEUROD1, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1 and PTF1α) or associated with terminally committed pancreatic cells (CHGA, CHGB, GAD2, GCG, HNF6α, INS, KRT19, SYP) in 17 PDAC cell lines and in frozen tumor samples from 41 PDAC patients. RESULTS: High baseline levels of the ISL1, KRT19, PAX6 and PDX1 mRNAs in PDAC cell lines, were risk factors for time-dependent xenograft appearance after subcutaneous injection in CD1-Nude mice. Consistently, in human PDAC samples, high levels of KRT19 mRNA were associated with reduced overall survival and earlier recurrence. Higher levels of PDX1 or PAX6 mRNAs were instead associated with a higher frequency of local recurrence. CONCLUSIONS: Our findings suggest that selected factors associated with pancreas development or its terminal differentiation might be implicated in mechanisms of PDAC progression and/or metastatic spread and that the measurement of their mRNA in tumors might be potentially used to improve patient prognostic stratification and prediction of the relapse site.
- Silencing of TRPM8 inhibits aggressive tumor phenotypes and enhances gemcitabine sensitivity in pancreatic cancer
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;18(8):935-944
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30316690
The transient receptor potential TRPM8 ion channel is required for cellular proliferation in pancreatic epithelia and adenocarcinoma. To elucidate the mechanism that mediates the function of TRPM8, we examined its role in the proliferation and invasion of pancreatic cancer (PC) cells. TRPM8 expression increased in both the PC tissues and cell lines; a high TRPM8 expression was correlated with poorer prognosis in patients with PC. In PC cell lines, PACN-1 and BxPC-3, Ca2+ influxes could be evoked by TRPM8; the sensitivity of PC cells to gemcitabine was increased, while the proliferation and invasion of PC cells were suppressed after RNA interference-mediated silencing of TRPM8. The mechanism of TRPM8 in gemcitabine-based chemotherapy was then investigated. The expression and activity of multidrug resistance-associated proteins, P-gp, MRP-2, LRP, was significantly reduced in response to TRPM8 silence. Moreover, TRPM8 knockdown significantly increased hENT1 protein levels and the ratio of Bax/Bcl-2 while decreased the protein levels of RRM1. Thus, TRPM8 is required for PC cell proliferation and invasion and was closely related to the gemcitabine sensitivity of PC. The modulation of TRPM8 expression may help improve treatment response of PC by combining with traditional chemotherapy.
- The receptor for advanced glycation end products: A fuel to pancreatic cancer
Seminars in cancer biology 2018 04;49():37-43
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28811077
The receptor for advanced glycation end products (RAGEs) was first illustrated in the year 1992. RAGE is a single-transmembrane and multi-ligand component of the immunoglobulin protein super family. The engagement of RAGE turns out to an establishment of numerous intracellular signalling mechanisms resulting in the progression and perpetuation of many types of cancer including, the pancreatic cancer. The present review primarily focuses on the multi-ligand activation of RAGEs leading to the downstream signalling cascade activation. The kick start of the RAGEs activation leads to the several anomalies and includes multiple types of cancers. The RAGE expression correlates well with the survival of pancreatic cancer cells leading to the myeloid response. RAGEs assist in the tumourogenesis which enhance and thrive to its fullest in the stressed tumour microenvironment. An improved perceptive of its involvement in pancreatic cancer may offer novel targets for tumour supervision and risk measurement.
Pancreatitis & Other Diseases
Molecular Studies on Pancreatitis & Other Diseases
- The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206869
Molecular Techniques & Research Methods, Liquid Biopsy
Molecular Techniques & Research Methods, Liquid Biopsy
- ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy
https://www.nature.com/articles/s41389-018-0096-9
- Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma
Annals of surgery 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30394883
OBJECTIVE: The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles. SUMMARY BACKGROUND DATA: FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed. METHODS: We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin. RESULTS: Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability. CONCLUSIONS: Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
- Liquid biopsy-based biomarkers for early detection of pancreatic cancer
http://pcm.amegroups.com/article/view/4588
Molecular Research on Microenvironment
Tumor Stroma Interactions, Microenvironment, Inflammatory Response, Microbiome
- EZH2-Mediated microRNA-139-5p Regulates Epithelial-Mesenchymal Transition and Lymph Node Metastasis of Pancreatic Cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182224/
- The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer
http://www.thno.org/v08p5072.pdf
- HH1-1, a novel Galectin-3 inhibitor, exerts anti-pancreatic cancer activity by blocking Galectin-3/EGFR/AKT/FOXO3 signaling pathway
https://www.sciencedirect.com/science/article/pii/S0144861718311846
- KRAS RENAISSANCE(S) in Tumor Infiltrating B Cells in Pancreatic Cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156365/
- Targeting Purinergic Receptor P2Y2 prevents the growth of pancreatic ductal adenocarcinoma by inhibiting cancer cell glycolysis
Clinical cancer research : an official journal of the American Association for Cancer Research 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30420446
PURPOSE: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. EXPERIMENTAL DESIGN: Expression of P2RY2 was determined in 264 human PDAC samples, and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. RESULTS: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevating expression of c-Myc and HIF1a, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacological inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. Additionally, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. CONCLUSIONS: These findings revealed the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.
- The microbiome of pancreatic cancer: from molecular diagnostics to new therapeutic approaches to overcome chemoresistance caused by metabolic inactivation of gemcitabine
Expert review of molecular diagnostics 2018 Nov;():1-5
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30392417
Pancreatic cancer is a complex disease, with an extremely poor response to chemotherapy. Emerging evidence indicates that the tumor microenvironment (TME) might play an important role in mediating chemoresistance. Areas covered: The evaluated study by Geller and collaborators describes several bacterial species within pancreatic tumor tissues and TME and investigated their roles in gemcitabine chemoresistance. Intratumor bacteria express the enzyme cytidine deaminase (CDD), whose long form (CDDL) was shown to metabolize gemcitabine into its inactive metabolite. CDDL is mostly expressed by Gammaproteobacteria and this was among the most common species in pancreatic cancer tissues. Interestingly, mouse models of colorectal cancer injected with bacterial CDDL displayed a reduced response to gemcitabine, but this resistance was neutralized by the antibiotic ciprofloxacin. Expert Commentary: The increased knowledge on the microbiome in pancreatic tissues, as well as its role in chemoresistance, will provide innovative prognostic and therapeutic strategies.
- MicroRNA let-7d targets thrombospondin-1 and inhibits the activation of human pancreatic stellate cells
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30393009
OBJECTIVES: The microRNA (miRNA) let-7d is linked to the formation of pancreatic cancer-related fibrosis. In this study, the mechanism by which let-7d regulates the activation of the human pancreatic stellate cell (hPSC) was evaluated. METHODS: The transient transfection of a let-7d mimic in the hPSCs was performed, and the altered thrombospondin 1 (THBS1) expression was confirmed by western blotting and real-time qPCR. Targeting of the 3’-untranslated region (UTR) of THBS1 by let-7d was investigated by the luciferase assays. After hPSC transfection using THBS1 siRNA, the fibrosis markers (α-SMA and collagen 1A1) were evaluated by western blotting and real-time qPCR. The correlation between tumor fibrosis and let-7d or THBS1 was estimated using the data from The Cancer Genome Atlas project. Finally, the effects of genistein on the hPSCs were evaluated. RESULTS: We found that a let-7d mimic inhibits THBS1 expression by targeting its 3’-UTR. THBS1 inhibition by siRNA inhibited hPSC activation. An in silico analysis revealed that let-7d and THBS1 expression are negatively correlated. Additionally, let-7d was negatively correlated with the stromal score, while THBS1 was positively correlated with this score. Genistein substantially induced let-7d and decreased the expression of fibrosis marker along with the inhibition of THBS1. CONCLUSIONS: Let-7d inhibited hPSC activation by targeting THBS1. Genistein induced the expression of let-7d and might modulate pancreatic fibrosis.
- GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2018 03;32(3):1170-1183
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29092903
The microenvironment of pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) generated by pancreatic cancer-associated fibroblasts (CAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). Using an unbiased GPCRomic array approach, we identified 82 G-protein-coupled receptors (GPCRs) commonly expressed by CAFs derived from 5 primary PDAC tumors. Compared with PSCs and PFs, CAFs have increased expression of GPR68 (a proton-sensing GPCR), with the results confirmed by immunoblotting, The Cancer Genome Atlas data, and immunohistochemistry of PDAC tumors. Co-culture of PSCs with PDAC cells, or incubation with TNF-α, induced GPR68 expression. GPR68 activation (by decreasing the extracellular pH) enhanced IL-6 expression via a cAMP/PKA/cAMP response element binding protein signaling pathway. Knockdown of GPR68 by short interfering RNA diminished low pH-induced production of IL-6 and enhancement of PDAC cell proliferation by CAF conditioned media. CAFs from other gastrointestinal cancers also express GPR68. PDAC cells thus induce expression by CAFs of GPR68, which senses the acidic microenvironment, thereby increasing production of fibrotic markers and IL-6 and promoting PDAC cell proliferation. CAF-expressed GPR68 is a mediator of low-pH-promoted regulation of the tumor microenvironments, in particular to PDAC cell-CAF interaction and may be a novel therapeutic target for pancreatic and perhaps other types of cancers.-Wiley, S. Z., Sriram, K., Liang, W., Chang, S. E., French, R., McCann, T., Sicklick, J., Nishihara, H., Lowy, A. M., Insel, P. A. GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells.
- E‑cadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT
Oncology reports 2018 Sep;40(3):1641-1649
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29956814
The aim of the present study was to research the effect of microenvironmental change on epithelial‑mesenchymal transition (EMT) in pancreatic cancer cells and to determine the correlation between E‑cadherin expression and the prognosis of pancreatic cancer patients. We established hypoxic, serum‑deficient and TGF‑β‑induced microenvironment models of pancreatic cancer cells and studied the changes in the mRNA and protein expression of EMT‑related molecules, E‑cadherin and vimentin, using western blot analysis and real‑time PCR. Furthermore, immunohistochemistry was used to investigate E‑cadherin expression in pancreatic cancer tissues, and survival analysis and COX regression analysis were conducted. In pancreatic cancer cells under hypoxic, serum‑starved and TGF‑β‑induced microenvironments, E‑cadherin protein and mRNA levels were significantly decreased (P<0.05), while vimentin protein and mRNA expression levels were significantly increased (P<0.05). The results of immunohistochemistry showed that the protein level of E‑cadherin in pancreatic cancer tissues was positively correlated with overall survival (P<0.01). The results of Cox regression analysis showed that E‑cadherin was an independent prognostic factor in pancreatic cancer. In conclusion, E‑cadherin expression was significantly decreased by microenvironment changes, and this decrease induced EMT in pancreatic cancer cells. E‑cadherin is an independent prognostic marker in pancreatic cancer patients.
- Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer
https://gut.bmj.com/content/early/2018/11/10/gutjnl-2018-317570
- From Friend to Enemy: Dissecting the Functional Alteration of Immunoregulatory Components during Pancreatic Tumorigenesis
https://www.mdpi.com/1422-0067/19/11/3584
Preneoplastic and Preinvasive Lesions
Molecular Pathology Preneoplastic and Preinvasive Lesions, PanIN, IPMN, MCN, ICPN
- Single‐cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions
https://onlinelibrary.wiley.com/doi/abs/10.1002/path.5194
- Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions
The Journal of pathology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30430578
Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions.
- Single Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression
Clinical cancer research : an official journal of the American Association for Cancer Research 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30385653
PURPOSE: Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically, intraductal papillary mucinous neoplasms (IPMNs) represent a bona fide pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneity that accompany multistep progression from non-invasive IPMNs to PDAC. METHODS: Single cell RNA-sequencing was performed through droplet-based sequencing on 5,403 cells from two low-grade IPMNs (LGD-IPMN), two high-grade IPMNs (HGD-IPMN), and two PDACs (all surgically resected). RESULTS: Analysis of single cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of non-invasive dysplasia to invasive cancer. While HGD-IPMNs expressed many core-signaling pathways described in PDAC, LGD-IPMNs harbored subsets of single cells with a transcriptomic profile that overlapped with invasive cancer. Notably, a pro-inflammatory immune component was readily seen in low-grade IPMNs, comprised of cytotoxic T-cells, activated T-helper cells, and dendritic cells, which was progressively depleted during neoplastic progression, accompanied by infiltration of myeloid-derived suppressor cells. Finally, stromal myofibroblast populations were heterogeneous, and acquired a previously described tumor-promoting and immune-evading phenotype during invasive carcinogenesis. CONCLUSIONS: This study demonstrates the ability to perform high resolution profiling of the transcriptomic changes that occur during multistep progression of cystic PDAC precursors to cancer. Notably, single cell analysis provides an unparalleled insight into both the epithelial and microenvironmental heterogeneity that accompany early cancer pathogenesis, and might be a useful substrate to identify targets for cancer interception.
- Single‐cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions
https://onlinelibrary.wiley.com/doi/abs/10.1002/path.5194?af=R&
SPN
Solid Pseudopapillary Neoplasm
- Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas
https://onlinelibrary.wiley.com/doi/abs/10.1002/path.5180
- Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas
The Journal of pathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30306561
Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low-grade malignant neoplasms that metastasise to the liver or peritoneum in 10-15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole-exome sequencing and copy-number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high-coverage targeted sequencing of 409 genes. In addition to CTNNB1-activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro-proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α-regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Animal Studies
- RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer
Cancer cell 2018 Nov;34(5):757-774.e7
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30423296
Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.
- β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer
Cancer cell 2018 01;33(1):75-90.e7
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29249692
Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.
- Host IDO2 Gene Status Influences Tumor Progression and Radiotherapy Response in KRAS-Driven Sporadic Pancreatic Cancers
Clinical cancer research : an official journal of the American Association for Cancer Research 2018 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30266763
Purpose: Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately affect cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2 in humans is the high prevalence of two inactivating single-nucleotide polymorphisms (SNP), which affords the opportunity to carry out loss-of-function studies directly in humans. In this study, we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment.Experimental Design: Transgenic Ido2+/+ and Ido2-/- mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (N = 200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression, and clinical survival data.Results: PDAC development was notably decreased in the Ido2-/- mice (30% vs. 10%, P < 0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P < 0.01), a treatment modality that has been highly debated due to its variable efficacy.Conclusions: The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2 genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.
- Levels of the Autophagy Related 5 Protein Affect Progression and Metastasis of Pancreatic Tumors in Mice
Gastroenterology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30296435
BACKGROUND AND AIMS: Cells in pancreatic ductal adenocarcinoma (PDAC) undergo autophagy, but its effects vary with tumor stage and genetic factors. We investigated the consequences of varying levels of the autophagy related 5 (Atg5) protein on pancreatic tumor formation and progression. METHODS: We generated mice that express oncogenic Kras in primary pancreatic cancer cells and have homozygous disruption of Atg5 (A5;Kras) or heterozygous disruption of Atg5 (A5+/-;Kras), and compared them with mice with only oncogenic Kras (controls). Pancreata were analyzed by histology and immunohistochemistry. Primary tumor cells were isolated and used to perform transcriptome, metabolome, intracellular calcium, extracellular cathepsin activity, and cell migration and invasion analyses. The cells were injected into wildtype littermates, and orthotopic tumor growth and metastasis were monitored. Atg5 was knocked down in pancreatic cancer cell lines using small hairpin RNAs; cell migration and invasion were measured, and cells were injected into wildtype littermates. PDAC samples were obtained from independent cohorts of patients and protein levels were measured on immunoblot and immunohistochemistry; we tested the correlation of protein levels with metastasis and patient survival times. RESULTS: A5+/-;Kras mice, with reduced Atg5 levels, developed more tumors and metastases, than control mice, whereas A5;Kras mice did not develop any tumors. Cultured A5+/-;Kras primary tumor cells were resistant to induction and inhibition of autophagy, had altered mitochondrial morphology, compromised mitochondrial function, changes in intracellular Ca2+ oscillations, and increased activity of extracellular cathepsin L and D. The tumors that formed in A5+/-;Kras mice contained greater numbers of type 2 macrophages than control mice, and primary A5+/-;Kras tumor cells had upregulated expression of cytokines that regulate macrophage chemoattraction and differentiation into M2 macrophage. Knockdown of Atg5 in pancreatic cancer cell lines increased their migratory and invasive capabilities, and formation of metastases following injection into mice. In human PDAC samples, lower levels of ATG5 associated with tumor metastasis and shorter survival time. CONCLUSIONS: In mice that express oncogenic Kras in pancreatic cells, heterozygous disruption of Atg5 and reduced protein levels promotes tumor development, whereas homozygous disruption of Atg5 blocks tumorigenesis. Therapeutic strategies to alter autophagy in PDAC should consider the effects of ATG5 levels to avoid the expansion of resistant and highly aggressive cells.
- SWI/SNF component ARID1A restrains pancreatic neoplasia formation
Gut 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30315093
OBJECTIVE: ARID1A is commonly mutated in pancreatic ductal adenocarcinoma (PDAC), but the functional effects of ARID1A mutations in the pancreas are unclear. Understanding the molecular mechanisms that drive PDAC formation may lead to novel therapies. DESIGN: Concurrent conditional Arid1a deletion and Kras activation mutations were modelled in mice. Small-interfering RNA (siRNA) and CRISPR/Cas9 were used to abrogate ARID1A in human pancreatic ductal epithelial cells. RESULTS: We found that pancreas-specific Arid1a loss in mice was sufficient to induce inflammation, pancreatic intraepithelial neoplasia (PanIN) and mucinous cysts. Concurrent Kras activation accelerated the development of cysts that resembled intraductal papillary mucinous neoplasm. Lineage-specific Arid1a deletion confirmed compartment-specific tumour-suppressive effects. Duct-specific Arid1a loss promoted dilated ducts with occasional cyst and PDAC formation. Heterozygous acinar-specific Arid1a loss resulted in accelerated PanIN and PDAC formation with worse survival. RNA-seq showed that Arid1a loss induced gene networks associated with Myc activity and protein translation. ARID1A knockdown in human pancreatic ductal epithelial cells induced increased MYC expression and protein synthesis that was abrogated with MYC knockdown. ChIP-seq against H3K27ac demonstrated an increase in activated enhancers/promoters. CONCLUSIONS: Arid1a suppresses pancreatic neoplasia in a compartment-specific manner. In duct cells, this process appears to be associated with MYC-facilitated protein synthesis.
- ZIP4 Promotes Muscle Wasting and Cachexia in Mice with Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells
Gastroenterology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30342032
BACKGROUND & AIMS: Cachexia, which includes muscle wasting, is a frequent complication of pancreatic cancer. There are no therapies that reduce cachexia and increase patient survival, so it is important to learn more about its mechanisms. The zinc transporter ZIP4 promotes growth and metastasis of pancreatic tumors. We investigated its effects on muscle catabolism via extracellular vesicle (EV)-mediated stimulation of mitogen-activated protein kinase 14 (p38MAPK). METHODS: We studied nude mice with orthotopic tumors grown from human pancreatic cancer cell lines (AsPC-1 and BxPC-3); tumors were removed 8 days after cell injection and analyzed by histology. Mouse survival was analyzed by Kaplan-Meier curves. ZIP4 was knocked down in AsPC-1 and BxPC-3 cells with small hairpin RNAs; cells with empty vectors were used as controls. Muscle tissues were collected from mice and analyzed by histology and immunohistochemistry. Conditioned media from cell lines and 3-dimensional spheroid/organoid cultures of cancer cells was applied to C2C12 myotubes. The myotubes and the media were analyzed by immunoblots, ELISAs, and immunofluorescence microscopy. EVs were isolated from conditioned media and analyzed by immunoblots. RESULTS: Mice with orthotopic tumors grown from pancreatic cancer cells with knockdown of ZIP4 survived longer and lost less body weight and muscle mass than mice with control tumors. Conditioned media from cancer cells activated p38MAPK and induced expression of F-box protein 32 and UBR2 in C2C12 myotubes, and also led to loss of myofibrillar protein myosin heavy chain and myotube thinning. Knockdown of ZIP4 in cancer cells reduced these effects. ZIP4 knockdown also reduced pancreatic cancer cell release of HSP70 and HSP90, which are associated with EVs, by decreasing CREB-regulated expression of RAB27B. CONCLUSIONS: ZIP4 promotes growth of orthotopic pancreatic tumors in mice and loss of muscle mass by activating CREB-regulated expression of RAB27B, required for release of EVs from pancreatic cancer cells. These EVs activate p38MAPK and induce expression of F-box protein 32 and UBR2 in myotubes, leading to loss of myofibrillar myosin heavy chain and myotube thinning. Strategies to disrupt these pathways might be developed to reduce pancreatic cancer progression and accompanying cachexia.
- DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth
Gut 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30343272
BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis. DESIGN: We analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity. RESULTS: We showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling. CONCLUSIONS: These findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.
- Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice
Gastroenterology 2018 10;155(4):1250-1263.e5
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29928898
BACKGROUND & AIMS: Pancreatitis after endoscopic retrograde cholangiopancreatography (PEP) is thought to be provoked by pancreatic ductal hypertension, via unknown mechanisms. We investigated the effects of hydrostatic pressures on the development of pancreatitis in mice. METHODS: We performed studies with Swiss Webster mice, B6129 mice (controls), and B6129 mice with disruption of the protein phosphatase 3, catalytic subunit, βisoform gene (Cnab-/- mice). Acute pancreatitis was induced in mice by retrograde biliopancreatic ductal or intraductal infusion of saline with a constant hydrostatic pressure while the proximal common bile duct was clamped -these mice were used as a model of PEP. Some mice were given pancreatic infusions of adeno-associated virus 6-nuclear factor of activated T-cells-luciferase to monitor calcineurin activity or the calcineurin inhibitor FK506. Blood samples and pancreas were collected at 6 and 24 hours and analyzed by enzyme-linked immunosorbent assay, histology, immunohistochemistry, or fluorescence microscopy. Ca2+ signaling and mitochondrial permeability were measured in pancreatic acinar cells isolated 15 minutes after PEP induction. Ca2+-activated phosphatase calcineurin within the pancreas was tracked in vivo over 24 hours. RESULTS: Intraductal pressures of up to 130 mm Hg were observed in the previously reported model of PEP; we found that application of hydrostatic pressures of 100 and 150 mm Hg for 10 minutes consistently induced pancreatitis. Pancreatic tissues had markers of inflammation (increased levels of interleukin [IL] 6, IL1B, and tumor necrosis factor), activation of signal transducer and activator of transcription 3, increased serum amylase and IL6, and loss of tight junction integrity. Transiently high pressures dysregulated Ca2+ processing (reduced Ca2+ oscillations and an increased peak plateau Ca2+ signal) and reduced the mitochondrial membrane potential. We observed activation of pancreatic calcineurin in the pancreas in mice. Cnab-/- mice, which lack the catalytic subunit of calcineurin, and mice given FK506 did not develop pressure-induced pancreatic inflammation, edema, or loss of tight junction integrity. CONCLUSIONS: Transient high ductal pressure produces pancreatic inflammation and loss of tight junction integrity in a mouse model of PEP. These processes require calcineurin signaling. Calcineurin inhibitors might be used to prevent acute pancreatitis that results from obstruction.
- Elastography can map the local inverse relationship between shear modulus and drug delivery within the pancreatic ductal adenocarcinoma microenvironment
Clinical cancer research : an official journal of the American Association for Cancer Research 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30352906
PURPOSE: High tissue pressure prevents chemotherapeutics from reaching the core of pancreatic tumors. Therefore, targeted therapies have been developed to reduce this pressure. While point probes have shown the effectiveness of these pressure-reducing therapies via single location estimates, ultrasound elastography is now widely available as an imaging technique to provide real-time spatial maps of shear modulus (tissue stiffness). However, the relationship between shear modulus and the underlying tumor microenvironmental causes has not been investigated. In this work, elastography was used to investigate how shear modulus influences drug delivery in situ, and how it correlates with collagen density, hyaluronic acid content, and patent vessel density, features of the tumor microenvironment known to influence tissue pressure. EXPERIMENTAL DESIGN: Intravenous injection of verteporfin, an approved human fluorescent drug, was used in two pancreatic cancer xenograft models (AsPC1 (n=25) and BxPC-3 (n=25)). RESULTS: Fluorescence intensity was higher in AsPC-1 tumors than in BxPC-3 tumors (p < 0.0001). Comparing drug uptake images and shear wave elastographic images with histological images revealed that: (1) drug delivery and shear modulus were inversely related, (2) shear modulus increased linearly with increasing collagen density, and (3) shear modulus was marginally correlated with the local assessment of hyaluronic acid content. CONCLUSIONS: These results demonstrate that elastography could guide targeted therapy and/or identify patients with highly elevated tissue pressure.
Bile Ducts
- Recurrent Mutations in APC and CTNNB1 and Activated Wnt/β-catenin Signaling in Intraductal Papillary Neoplasms of the Bile Duct A Whole Exome Sequencing Study
https://journals.lww.com/ajsp/Abstract/2018/12000/Recurrent_Mutations_in_APC_and_CTNNB1_and.11.aspx
- Comprehensive analysis of long noncoding RNA-associated competing endogenous RNA network in cholangiocarcinoma
Biochemical and biophysical research communications 2018 Dec;506(4):1004-1012
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30404735
BACKGROUND: Long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which can largely influence on tumorigenesis and tumor progression. However, the role of lncRNA-mediated ceRNAs in cholangiocarcinoma (CCA) remains unknown. This study aimed to develop novel lncRNAs as well as their action mechanisms in CCA. METHODS: The expression profiles of lncRNAs, miRNAs, and mRNAs of 36 CCA tissues and 9 non-tumor bile duct tissues were obtained from The Cancer Genome Atlas (TCGA) database. The differentially expressed RNAs werre identified using the DESeq package in R. The ceRNA network was constructed in CCA based on bioinformatics generated from miRcode, miRTarBase, miRDB, and TargetScan. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using “DAVID 6.8” and R packages “Clusterprofile”. Survival analysis was performed based on Kaplan-Meier curve analysis. RESULTS: We identified a total of 1411 differentially expressed lncRNAs, 3494 mRNAs, and 64 miRNAs between CCA and matched normal tissues. By combining the data predicted by databases with intersection RNAs, a lncRNA-miRNA-mRNA ceRNA network consisting of 116 lncRNAs, 14 miRNAs and 59 mRNAs was established. According to the survival analysis, we detected 11 DElncRNA to have a significant impact on the overall survival in patients with CCA (P < 0.05). CONCLUSIONS: Our study identified novel lncRNAs associated with CCA progression and prognosis and provided data to further understand lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of CCA.
- Over-expression of TNNI3K is associated with early-stage carcinogenesis of cholangiocarcinoma
Molecular carcinogenesis 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30334579
Cholangiocarcinoma (CCA) is a devastating disease with very poor prognosis due to late diagnosis and resistance to traditional chemotherapies and radiotherapies. Herein, thioacetamide (TAA)-induced rat CCA model and CGCCA cell line were used; we aim to study the cytogenetic features during tumoral development of CCA and uncover the mystery regarding carcinogenesis of CCA. The Array comparative genomic hybridization analysis, in silico method, gene knockdown, Western blot, cell count proliferation assay, clonogenecity assay, and IHC staining were applied in this study. Array comparative genomic hybridization analysis was performed on all different TAA-induced phases of rat tissues to reveal the certain pattern, +2q45, +Xq22, -12p12, have been identified for the tumor early stage, where involve the gene TNNI3K. In addition, 16 genes and 3 loci were associated with rapid tumor progression; JAK-STAT signaling pathway was highly correlated to late stage of CCA. In silico database was used to observe TNNI3K was highly express at tumor part compared with normal adjacent tissue in CCA patients from TCGA dataset. Furthermore, the growth of TNNI3K-knockdown SNU308 and HuCCT1 cells decreased when compared with cells transfected with an empty vector cell demonstrated by proliferation and colonogenecity assay. Besides, over expression of TNNI3K was especially confirmed on human CCA tumors and compared with the intrahepatic duct stone bile duct tissues and normal bile duct tissues (P < 0.001). Our findings might uncover the mystery regarding carcinogenesis of CCA, and provide the potential genetic mechanism to the clinicians some ideas for the patients’ treatment.
- Evaluation of NCAM and c-Kit as hepatic progenitor cell markers for intrahepatic cholangiocarcinomas
Pathology, research and practice 2018 Dec;214(12):2011-2017
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30301635
BACKGROUND: Intrahepatic cholangiocarcinomas (ICCs) are primary liver malignancies and are the second most common type of malignancy after hepatocellular carcinoma. ICCs are heterogeneous in clinical features, genotype, and biological behavior, suggesting that ICCs can initiate in different cell lineages. AIM: We investigated intrahepatic cholangiocarcinoma RBE cell lines for the markers neural cell adhesion molecule (NCAM) and c-Kit, which possess hepatic progenitor cells properties. METHODS: NCAM + c-Kit + cells were tested for hepatic progenitor cell properties including proliferation ability, colony formation, spheroid formation, and invasiveness in NOD/SCID mice. The Agilent Whole Human Genome Microarray Kit was used to evaluate differences in gene expression related to stem cell signaling pathways between NCAM + c-Kit + and NCAM-c-Kit- subset cells. Microarray results were further confirmed by real-time RT-PCR. RESULTS: NCAM + c-Kit + cells showed hepatic progenitor cell-like traits including the abilities to self-renew and differentiate and tumorigenicity in NOD/SCID mice. Differences were observed in the expression of 421 genes related to stem cell signaling pathways (fc ≥ 2 or fc ≤ 0.5), among which 231 genes were upregulated and 190 genes were downregulated. CONCLUSION: NCAM + c-Kit + subset cells in RBE may have properties of hepatic progenitor cells. NCAM combined with c-Kit may be a valuable marker for isolating and purifying ICC stem/progenitor cells.
Gallbladder
- Regional differences in gallbladder cancer pathogenesis: Insights from a multi‐institutional comparison of tumor mutations
https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.31850
- Molecular Diagnostics in Pancreatic and Biliary Cytology
https://link.springer.com/chapter/10.1007/978-3-319-97397-5_15
- Regional differences in gallbladder cancer pathogenesis: Insights from a multi-institutional comparison of tumor mutations
Cancer 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30427539
BACKGROUND: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.
Ampulla of Vater
- Ampullary carcinoma-A genetic perspective
Mutation research 2018 03;776():10-22
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29807574
Ampulla of vater carcinoma (AVC) is a rare gastrointestinal tumour that is associated with a high mortality rate and it’s often diagnosed at later stages due to lack of clinical symptoms. Early diagnosis of this condition is essential to effectively treat patients for better prognosis. A significant amount of advancement has been made in understanding the molecular nature of cancer in the past decade. A substantial number of mutations and alterations have been detected in various tumors. Despite the occurrence of AVC across the globe, the number of studies conducted on this tumor type remains low; this is largely due to its rare occurrence. Moreover, AVC tissues are complex and contain mutations in oncogenes, tumour suppressors, apoptotic proteins, cell proliferation proteins, cell signaling proteins, transcription factors, chromosomal abnormalities and cellular adhesion proteins. The frequently mutated genes included KRAS, TP53 and SMAD4 and are associated with prognosis. Several molecules of the PI3K, Wnt signaling, TGF-beta pathway and cell cycle have also been altered in AVCs. This review comprises of all the genetic mutations, associated pathways and related prognosis that are involved in AVCs from the year 1989 to 2017. This report can be used as a stepping-stone to establish biomarkers for early diagnosis of AVC and to discover molecular targets for drug therapy.
- Adenosquamous carcinoma of the papilla of Vater: A phenotypic heterogeneity characterized by a common molecular landscape
Pathology international 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30417956
- Ampulla of Vater carcinoma: Molecular landscape and clinical implications
World journal of gastrointestinal oncology 2018 Nov;10(11):370-380
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30487949
Ampulla of Vater is a peculiar anatomical structure, characterized by the crossroad of three distinct epithelia: Intestinal, ductal pancreatic and biliary. Adenocarcinomas arising in this area represent an opportunity to understand the comparative biology of all periampullary malignancies. These neoplasms can exhibit intestinal, pancreaticobiliary or mixed features, whereas the subclassification based on morphology and immunohistochemical features failed in demonstrating a robust prognostic reliability. In the last few years, the molecular landscape of this tumor entity has been uncovered, identifying alterations that may serve as prognostic and predictive biomarkers. In this review, the histological and genetic characteristics of ampullary carcinomas are discussed, taking into account the main clinical and therapeutic implications related to this tumor type as well.
- MiR-21 up-regulation in ampullary adenocarcinoma and its pre-invasive lesions
Pathology, research and practice 2018 Jun;214(6):835-839
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29731265
Poor information is available on the molecular landscape characterizing the carcinogenetic process leading to ampullary carcinoma. MiR-21 is one of the most frequently up-regulated miRNAs in pancreatic adenocarcinoma, a tumor sharing similar molecular features with ampullary adenocarcinomas (AVCs), above all with the pancreatic-biliary type. We profiled, by in situ hybridization (ISH), miR-21 expression in a series of 26 AVCs, 50 ampullary dysplastic lesions (35 low-grade [LG-IEN] and 15 high-grade [HG-IEN]) and 10 normal duodenal mucosa samples. The same series was investigated by immunohistochemistry for β-catenin, p53 and HER2 expression. HER2 gene amplification was evaluated by chromogenic in situ hybridization. To validate miR-21 ISH results we performed miR-21 qRT-PCR analysis in a series of 10 AVCs and their matched normal samples. All the normal control samples showed a negative or faint miR-21 expression, whereas a significant miR-21 up-regulation was observed during the carcinogenetic cascade (p < 0.001), with 21/26 (80.8%) of cancer samples showing a miR-21 overexpression. In comparison to control samples, a significant overexpression was found in samples of LG-IEN (p = .0003), HG-IEN (p = .0001), and AVCs (p < 0.0001). No significant difference in miR-21 overexpression was observed between LG-IEN, HG-IEN and AVCs. By qRT-PCR analysis, AVCs showed a 1.7-fold increase over the controls (p = .003). P53 was frequently dysregulated in both dysplastic and carcinoma samples (44 out of 76; 57.9%). A 20% (10/50) of dysplastic lesions and 11% (3/26) of carcinomas were characterized by a nuclear localization of β-catenin. Only 2 AVCs (7.7%; both intestinal-type) showed a HER2 overexpression (both 2+), which corresponded to a HER2 gene amplification at CISH analysis. This is the first study demonstrating a miRNA dysregulation in the whole spectrum of ampullary carcinogenesis. MiR-21 overexpression is an early molecular event during ampullary carcinogenesis and its levels increase with the neoplastic progression.
Neuroendocrine
- Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases
- Clinical and in vitro studies of the correlation between MGMT and the effect of streptozocin in pancreatic NET
https://link.springer.com/article/10.1007/s00280-018-3700-y
- Evaluating gastroenteropancreatic neuroendocrine tumors through microRNA sequencing
Endocrine-related cancer 2019 Jan;26(1):47-57
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30021866
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be challenging to evaluate histologically. MicroRNAs (miRNAs) are small RNA molecules that often are excellent biomarkers due to their abundance, cell-type and disease stage specificity and stability. To evaluate miRNAs as adjunct tissue markers for classifying and grading well-differentiated GEP-NETs, we generated and compared miRNA expression profiles from four pathological types of GEP-NETs. Using quantitative barcoded small RNA sequencing and state-of-the-art sequence annotation, we generated comprehensive miRNA expression profiles from archived pancreatic, ileal, appendiceal and rectal NETs. Following data preprocessing, we randomly assigned sample profiles to discovery (80%) and validation (20%) sets prior to data mining using machine-learning techniques. High expression analyses indicated that miR-375 was the most abundant individual miRNA and miRNA cistron in all samples. Leveraging prior knowledge that GEP-NET behavior is influenced by embryonic derivation, we developed a dual-layer hierarchical classifier for differentiating GEP-NET types. In the first layer, our classifier discriminated midgut (ileum, appendix) from non-midgut (rectum, pancreas) NETs based on miR-615 and -92b expression. In the second layer, our classifier discriminated ileal from appendiceal NETs based on miR-125b, -192 and -149 expression, and rectal from pancreatic NETs based on miR-429 and -487b expression. Our classifier achieved overall accuracies of 98.5% and 94.4% in discovery and validation sets, respectively. We also found provisional evidence that low- and intermediate-grade pancreatic NETs can be discriminated based on miR-328 expression. GEP-NETs can be reliably classified and potentially graded using a limited panel of miRNA markers, complementing morphological and immunohistochemistry-based approaches to histologic evaluation.
- Neuroendocrine neoplasia goes molecular — time for a change
https://www.nature.com/articles/s41571-018-0118-8
- Blood mRNA Measurement (NETest) for Neuroendocrine Tumors diagnosis of Image-negative liver metastatic disease
- Neuropilin-1 (NRP-1) upregulated by IL-6/STAT3 signaling contributes to invasion in pancreatic neuroendocrine neoplasms
Human pathology 2018 Nov;81():192-200
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30420046
Although the upregulation of Neuropilin-1 (NRP-1) is associated with many solid tumors, its role in pancreatic neuroendocrine neoplasms (pNEN) has not been well elucidated. The aim of this study was to investigate the role of NRP-1 in improving treatment and determining the prognosis of pNEN. In this study, the expression of NRP-1 in pNEN tissue samples and pNEN cell line BON1 was analyzed by Western blot, polymerase chain reaction (PCR) and immunocytochemistry upon exposure to interleukin-6 (IL-6). Additionally, pNEN cell line BON1 was transfected with small interfering RNAs against NRP-1 or signal transducer and activator of transcription 3 (STAT3) and assessed by in vitro invasion assays. The expression of NRP-1 in pNEN tissues was markedly increased compared with adjacent normal pancreatic tissues. High NRP-1 expression was strongly correlated with tumor grades (P = .026), lymph node metastasis (P = .025), and tumor-node-metastasis stages (P = .012). Furthermore, NRP-1 downregulation notably inhibited the metastatic capacity of pNEN cells, and STAT3 knockdown was found to downregulate the expression of NRP-1. BON1 cells upregulated NRP-1 expression upon stimulation with IL-6. This was accompanied by activation/phosphorylation of the AKT and STAT3 signaling pathways. Western blot of extracts of human pNENs confirmed increased NRP-1 expression, as well as AKT/STAT3 phosphorylation in tissue of pNENs with elevated expression levels of IL-6. In conclusion, our findings suggest that NRP-1 is upregulated in pNEN and is correlated with the metastatic capacity of pNEN cells, potentially via interaction with the IL-6/STAT3 signaling pathway.
- Cell-Free DNA From Metastatic Pancreatic Neuroendocrine Tumor Patients Contains Tumor-Specific Mutations and Copy Number Variations
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221938/
- Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases
Annals of surgery 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30339629
OBJECTIVE:: The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND: Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS: A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. RESULTS: In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. CONCLUSIONS: We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.
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Advances in Anatomic Pathology
American Journal of Clinical Pathology
The American Journal of Gastroenterology
The American Journal of Pathology
American Journal of Surgical Pathology
Annals of Diagnostic Pathology
Annals of Surgery
Annals of Surgical Oncology
Annual Review of Pathology-Mechanisms of Disease
APMIS
Applied Immunohistochemistry & Molecular Morphology
Archives of Pathology & Laboratory Medicine
Cancer
Cancer Cell
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Cell
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Clinical Cancer Research
Cochrane Database Systematic Reviews
Cytojournal
Cytopathology
Diagnostic Cytopathology
Diagnostic Pathology
Endocrine Pathology
Experimental and Molecular Pathology
Expert Review of Molecular Diagnostics
Gastroenterology
Gut
Histology and Histopathology
Histopathology
Human Pathology
International Journal of Surgical Pathology
International Journal of Clinical and Experimental Pathology
Journal of Clinical Pathology
Journal of Molecular Diagnostics
Journal of Pathology
Laboratory investigation
Lancet
Medical Molecular Morphology
Modern Pathology
Nature
Nature Reviews Gastroenterology & Hepatology
NEJM
Pancreas
Pancreatology
Pathobiology
Pathologie Biologie
Pathology
Pathology & Oncology Research
Pathology International
Pathology Research and Practice
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Seminars in Diagnostic Pathology
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Surgical pathology clinics
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Trends in Cancer
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